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10.3390/cancers15020507 | Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study | <jats:p>Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.</jats:p> | [
{
"section_content": "Ibrutinib is a once-daily oral Bruton tyrosine kinase (BTK) inhibitor that is approved as first-line treatment for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the United States, Europe, and other countries.Ibrutinib has the longest follow-up of any targeted therapy across multiple randomized phase 3 studies and is the only therapy to date that has demonstrated a significant overall survival (OS) benefit compared with chemotherapy/chemoimmunotherapy in patients with previously untreated CLL/SLL [1][2][3][4].Initial approval of ibrutinib in the first-line setting was supported by results from the primary analysis of the phase 3 RESONATE-2 study, which demonstrated that ibrutinib was superior to chlorambucil with respect to both efficacy and tolerability [5].With up to 8 years of follow-up (median: 82.7 months; range, 0.1-96.6months) in the RESONATE-2 study, the majority of ibrutinib-randomized patients remained progression-free; median progression-free survival (PFS) was not yet reached at the latest data cut [1]. Previous studies suggest that patients who continue treatment with single-agent ibrutinib experience better survival outcomes than patients who discontinue treatment within the first few years [6][7][8][9].Additionally, real-world evidence suggests that dose management (dose reduction or temporary dose holds for up to 1-2 weeks) results in improvement in or resolution of adverse events (AEs) [10] without impacting disease outcomes [6,[10][11][12][13][14][15][16][17][18].Therefore, active management of AEs by dose modification might facilitate continued ibrutinib treatment and maximize clinical outcomes [12].As of May 2022, the US prescribing information for ibrutinib includes updates to recommended dose modifications for AEs [19]. As it is the only BTK inhibitor with long-term follow-up for up to 8 years, we have the opportunity to examine efficacy and safety outcomes in patients with longer-term experience on ibrutinib treatment.Here, we describe characteristics and outcomes of patients who received treatment with ibrutinib for ≥5 years in the RESONATE-2 study. ",
"section_name": "Introduction",
"section_num": "1."
},
{
"section_content": "",
"section_name": "Materials and Methods",
"section_num": "2."
},
{
"section_content": "",
"section_name": "Study Design and Patients",
"section_num": "2.1."
},
{
"section_content": ") is a multicenter, international, randomized, open-label, phase 3 study designed to compare the efficacy and safety of first-line treatment with ibrutinib versus chlorambucil in patients aged ≥65 years with previously untreated CLL/SLL who required therapy per the 2008 International Workshop on CLL (iwCLL) criteria [20].Patients with del(17p) were excluded.Detailed methods were previously reported [5].Briefly, eligible patients were randomly assigned in a 1:1 ratio to receive oral ibrutinib 420 mg once daily until occurrence of progressive disease or unacceptable toxicity, or chlorambucil 0.5 mg/kg, escalated to a maximum of 0.8 mg/kg as tolerated, on days 1 and 15 of each 28-day cycle for up to 12 cycles.After confirmation of progressive disease per iwCLL criteria [20,21], patients who were randomly assigned to the chlorambucil arm could cross over to second-line treatment with ibrutinib.Per protocol, ibrutinib was temporarily held for any unmanageable grade ≥ 3 AE that was considered by the investigator to be potentially related to the study's treatment.Other AEs, including AEs of grade 2 in severity, could be managed with a one-level dose reduction of ibrutinib if the AE was considered to be potentially manageable by dose reduction as judged by the investigator. This study was performed in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki.The study protocol was approved by institutional review boards of each participating institution, and all patients provided written informed consent before participation in the study.This study was registered with ClinicalTrials.gov,numbers NCT01722487 and NCT01724346. ",
"section_name": "RESONATE-2 (PCYC-1115 [NCT01722487]/PCYC-1116 [NCT01724346]",
"section_num": null
},
{
"section_content": "The current exploratory analysis evaluated baseline demographics and clinical characteristics, overall response rates (per iwCLL criteria [20,21]), PFS, OS, prevalence of AEs over time, and AEs leading to dose modifications (per protocol) for ibrutinib-randomized patients who were on ibrutinib treatment for ≥5 years.Since the study protocol provided flexibility for dose reductions based on an investigator's judgment, additional analyses were performed to retrospectively determine the incidence of dose reductions due to AEs for which dose reductions are recommended in the recently updated US prescribing information (grade 2 cardiac failure, grade 3 cardiac arrhythmia, grade 3 or 4 nonhematologic AEs [excluding cardiac failure and cardiac arrhythmia], grade 3 or 4 neutropenia with infection or fever, and grade 4 hematologic AEs) [19]. Baseline characteristics were also evaluated as potential predictors for remaining on treatment for ≥5 years using a multivariate logistic regression model including the following baseline characteristics: age group, sex, Eastern Cooperative Oncology Group performance status, Cumulative Illness Rating Scale score, creatinine clearance, TP53 mutation status, IGHV mutation status, del(11q) status, disease histology, bulky disease, β-2 microglobulin, Rai stage, any history of cytopenia, lactate dehydrogenase level, and geographic region.Additionally, PFS and OS were analyzed in subgroups of patients with and without dose reductions in the overall population of all ibrutinib-treated patients; these exploratory post hoc analyses were not powered for significance, and comparative statistics are provided for descriptive purposes only.PFS and OS were estimated using the Kaplan-Meier method. ",
"section_name": "Analysis",
"section_num": "2.2."
},
{
"section_content": "In RESONATE-2, 269 patients were randomly assigned to receive ibrutinib (n = 136) or chlorambucil (n = 133).Of the 136 patients in the ibrutinib arm, 79 (58%) received ibrutinib treatment for ≥5 years.Median follow-up duration for patients who were on ibrutinib treatment for ≥5 years (n = 79) was 89.2 months (range: 61.3-96.6).Of these 79 patients, 22 subsequently discontinued ibrutinib in years 5-6 (n = 9), 6-7 (n = 10), or 7-8 (n = 3); reasons for discontinuation in these 22 patients were progressive disease (n = 10), death (n = 4), AEs (n = 3), physician decision (n = 3), and patient withdrawal (n = 2). ",
"section_name": "Results",
"section_num": "3."
},
{
"section_content": "Within ibrutinib-randomized patients in the intention-to-treat population (n = 136), baseline characteristics in the subset of patients who were on ibrutinib treatment for ≥5 years (n = 79) were generally similar to those in the subset of patients who were on ibrutinib treatment for <5 years (n = 57) (Table 1).Compared with the subset of patients who were on ibrutinib treatment for <5 years, the subset of patients who were on ibrutinib treatment for ≥5 years were more likely to be in the youngest age group (65-69 years; 37% vs. 19% of patients) and had a longer interval between initial diagnosis and initiation of study treatment (median 35 vs. 26 months). ",
"section_name": "Baseline Characteristics",
"section_num": "3.1."
},
{
"section_content": "In multivariate analysis, several baseline characteristics showed a trend toward continuation of ibrutinib treatment for ≥5 years (age ≤ 73 years, female sex, creatinine clearance ≥60 mL/min, TP53 mutated, del(11q), CLL histology, absence of bulky disease [<5 cm], β-2 microglobulin >3.5 mg/L, Rai stage III/IV, absence of cytopenia, and lactate dehydrogenase ≤250 U/L), but none reached statistical significance (Figure 1). ",
"section_name": "Predictors of Ibrutinib Treatment for ≥5 Years",
"section_num": "3.2."
},
{
"section_content": "Responses deepened over time, as indicated by the improvement of complete response (CR) rates from 10% (8/79 patients) at 1 year to 42% (33/79 patients) by 5 years and 46% (36/79 patients) by 7 years (Figure 2a).In patients who were on ibrutinib treatment for ≥5 years, 23/79 (29%) had a documented response of partial response with lymphocytosis (PR-L); of these patients, 9/23 (39%) achieved a best response of partial response (PR), 1/23 (4%) achieved nodular PR (nPR), and 13/23 (57%) achieved CR.In the overall population of ibrutinib-randomized patients, 30/136 (22%) had a documented response of PR-L; of these patients, 13/30 (43%) achieved a best response of PR, 1/30 (3%) achieved nPR, and 15/30 (50%) achieved CR.In patients who were on ibrutinib treatment for ≥5 years, the median time to PR was 4.6 months (95% CI: 3.8-7.4),whereas the median time to CR was 32.3 months (95% CI: 19.7-37.7)for those patients achieving CR.With up to 8 years of follow-up, complete response was achieved in 44 patients in the overall population, 36 of whom received ibrutinib treatment for ≥5 years. In patients who were on ibrutinib treatment for ≥5 years, median PFS and OS were not yet reached; 7-year PFS and OS rates were 82% (95% CI: 71-89) and 94% (95% CI: 86-97), respectively (Figure 2b,c). ",
"section_name": "Efficacy in Patients on Ibrutinib Treatment for ≥5 Years",
"section_num": "3.3."
},
{
"section_content": "In patients who were on ibrutinib treatment for ≥5 years, the median duration of ibrutinib treatment was 89.2 months (range: 60.4-96.6).Median relative dose intensity of ibrutinib for these patients was 98% (range: 47-100).The most frequent AEs of any grade across the entire study period were diarrhea (42/79 patients; 53%), cough (34/79; 43%), and upper respiratory tract infection (33/79; 42%).Prevalence of the most frequent AEs of any grade and of grade ≥ 3 were generally highest in years 0-1 and decreased over time thereafter (Figure 3a,b).Prevalence of AEs of clinical interest of any grade over time are shown in Supplementary Figure S1.AEs of any grade (occurring in ≥25% of patients overall) by yearly interval; (b) Most frequent grade ≥ 3 AEs (occurring in ≥5% of patients overall) by yearly interval.Prevalence was determined by the proportion of patients with a given AE (existing event or new onset of an event) during each yearly interval.Multiple onsets of the same AE term within a specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was counted in each of the intervals.Abbreviations: AE, adverse event; UTI, urinary tract infection; URTI, upper respiratory tract infection. ",
"section_name": "Prevalence of AEs over Time",
"section_num": "3.4."
},
{
"section_content": "AEs led to dose reductions in 16/79 patients (20%) who were on ibrutinib treatment for ≥5 years and in 31/135 patients (23%) in the overall population of all ibrutinib-treated patients (Table 2).Most patients (12/16; 75%) experienced only one AE leading to dose reduction. a Denominator is patients with dose reductions because of any AE.b The same patient may be counted in more than one category because of multiple AE events leading to dose reduction.c Of 12 AEs that recurred at same/higher grade at any point during treatment, 3/13 were infections, 2/13 were hematologic, 2/13 were cardiac, 1/13 was gastrointestinal, and 4/13 were other.Abbreviations: AE, adverse event; NR, not reached; SOC, system organ class. Among patients who were on ibrutinib treatment for ≥5 years, the lowest ibrutinib dose for most patients with dose reductions was 280 mg once daily (10/16 patients).At data cutoff, 3/16 patients were receiving ibrutinib 420 mg once daily, 10/16 were receiving 280 mg once daily, and 3/16 were receiving 140 mg once daily.The median duration of treatment with ibrutinib at a reduced dose was not reached (range: 8.4-84.0+months) for patients who were on ibrutinib treatment for ≥5 years compared with 36.1 months (range: 0.0-84.0+) in all ibrutinib-treated patients with dose reductions (n = 31). Following dose reduction, 13/16 patients (81%) had a resolution of the initial AE.Three patients had AEs that were not resolved at data cutoff (grade 3 malignant lung neoplasm, grade 2 fatigue, and grade 1 contusion in 1 patient each).When considering the subset of AEs for which dose reductions are recommended in the updated ibrutinib US prescribing information (as of May 2022), such AEs led to dose reductions in 4/79 patients (5%) (Table 3).Among these patients, AEs did not recur or recurred at a lower grade in 3/4 patients; 1 patient had recurrence at the same grade AE 3 years after initial resolution (grade 3 atrial fibrillation), that resolved without further dose reduction.Patients who were on ibrutinib treatment for <5 years (n = 56) experienced similar rates of AEs leading to dose reduction (15/56; 27%).Most common reasons for dose reduction by system organ class in this subgroup were hematologic (n = 3), cardiac (n = 3), and dermatologic (n = 3).Dose reductions were more common in response to grade 3 AEs (n = 8); however, 100% of AEs (15/15) were initially resolved.Six patients (40%) experienced a recurrence of their AE at the same or higher grade. AEs led to dose holds of ≥7 days in 45/79 patients (57%) who were on ibrutinib treatment for ≥5 years and in 79/135 patients (59%) in the overall population of all ibrutinibtreated patients (Table 4). Among patients who were on ibrutinib treatment for ≥5 years, ibrutinib was restarted at 420 mg once daily after dose holds of ≥7 days for most patients (42/45 patients).Following a dose hold of ≥7 days, 43/45 patients (96%) had resolution of the initial AE. Among patients who were on ibrutinib for ≥5 years, the frequency of AEs leading to dose reductions was highest in years 0-2 and lower in subsequent years, whereas the frequency of AEs leading to dose holds of ≥7 days remained relatively consistent across the first 6 years of treatment (Supplementary Figure S2).a The same patient may be counted in more than one category because of multiple AE events leading to dose holds; b Denominator is patients with dose holds ≥7 days because of any AE.Abbreviations: AE, adverse event; SOC, system organ class. ",
"section_name": "Dose Management with Ibrutinib Treatment",
"section_num": "3.5."
},
{
"section_content": "In the overall population of all ibrutinib-treated patients, median PFS for patients who had dose reductions (n = 31) was 87.7 months (95% CI: 56.9-NE) and was not reached (95% CI: 81.9-NE) for those without dose reductions (n = 104) (hazard ratio 0.96 [95% CI: 0.50-1.84];p = 0.9011; Figure 4a).Estimated 7-year PFS rates were 59% (95% CI: 39-74) and 59% (95% CI: 48-68) for patients with and without dose reductions, respectively.With up to 8 years of follow-up, median OS was not reached in either group (hazard ratio 1.28 [95% CI: 0.58-2.83];p = 0.5363; Figure 4b); estimated 7-year OS rates were 74% (95% CI: 54-86) and 79% (95% CI: 69-86) in patients with and without dose reductions, respectively. ",
"section_name": "Exploratory Post Hoc Analysis of Outcomes in Patients with Dose Reductions",
"section_num": "3.6."
},
{
"section_content": "Concomitant medications of clinical interest in patients who were on ibrutinib treatment for ≥5 years are shown in Supplementary Table S1.Anticoagulants and antiplatelet agents were frequently used during the treatment period (33% and 65%, respectively), as were antihypertensive medications, including agents acting on the renin-angiotensin system (61%), beta-blocking agents (46%), calcium channel blockers (35%), and other antihypertensives (10%).Overall, 67% of patients received medications to treat acid-related disorders, including proton pump inhibitors in 58% of patients. ",
"section_name": "Concomitant Medications",
"section_num": "3.7."
},
{
"section_content": "Results of the current analysis demonstrate that more than half of patients with previously untreated CLL/SLL were able to receive treatment with single-agent ibrutinib for ≥5 years.While real-world studies have suggested an increased risk of discontinuation of targeted therapies in patients with older age, higher comorbidity burden, higher tumor burden, and/or worse performance status at baseline [13,22,23], no individual baseline characteristics were identified as significant predictors for continuation of long-term ibrutinib treatment in the current study. Among patients who were on ibrutinib treatment for ≥5 years, responses deepened over time.This subgroup of patients had a higher CR rate over the course of the study (46%) relative to the overall population of ibrutinib-randomized patients (34%) [1], suggesting that patients with favorable responses may be more likely to continue on ibrutinib treatment.In line with this, a higher PFS rate at 7 years was seen in patients who remained on long-term ibrutinib treatment for ≥5 years (82%) relative to the overall ibrutinib-randomized population (59%) [1].These findings are consistent with those of previous studies, suggesting that continuation of ibrutinib treatment is associated with improved efficacy outcomes [6][7][8]. Safety results in patients who were on ibrutinib treatment for ≥5 years were consistent with those seen in the overall population of ibrutinib-treated patients, including incidences of AEs of clinical interest (hypertension, atrial fibrillation, and major hemorrhage) [1].AEs generally decreased over time with continued ibrutinib treatment, and no new safety signals emerged in patients who received ibrutinib treatment for ≥5 years.Treatment with ibrutinib was well tolerated irrespective of the frequent use of concomitant antithrombotics, antihypertensives, and acid-reducing agents.Since AEs are the most common reason for discontinuation of ibrutinib in the first-line setting [1,[23][24][25][26][27][28], optimization of AE management is crucial to enabling patients to remain on long-term therapy.In the subgroup of patients who were on ibrutinib treatment for ≥5 years, active management of AEs with dose reductions or dose holds was associated with AE resolution in the majority (>80%) of patients.Additionally, dose reductions helped to prevent recurrence or worsening of AEs for most patients, facilitating continued benefit from ibrutinib treatment. In the current study, disease assessments were performed at regularly scheduled intervals based on iwCLL criteria [20,21].With up to 8 years of follow-up in the RESONATE-2 study, PFS and OS were similar between patients with and without dose reductions in the overall population of ibrutinib-randomized patients.Patients who had dose reductions received reduced doses of ibrutinib for extended periods of time (median of 3 years in all ibrutinib-treated patients with dose reductions).Together, these results suggest that patients experiencing AEs leading to dose reduction continue to benefit from ibrutinib at the reduced dose.While two real-world studies found significantly worse PFS in patients receiving ibrutinib at reduced doses (<420 mg once daily), this finding from RESONATE-2 is consistent with several other studies that have found no significant difference in efficacy outcomes between patients with dose reductions due to AEs compared to patients without dose reductions [10,[12][13][14][15][16]29,30]. ",
"section_name": "Discussion",
"section_num": "4."
},
{
"section_content": "Regardless of demographic and disease characteristics at baseline, more than half (58%) of the patients randomly assigned to the ibrutinib arm in the RESONATE-2 study continued to benefit from ibrutinib treatment for ≥5 years.With up to 8 years of follow-up, the subset of patients who received ibrutinib treatment for ≥5 years experienced sustained efficacy benefits as evidenced by improved depth of response over time and high PFS rates. For patients who received ibrutinib treatment for ≥5 years, the safety profile was consistent with previous reports of long-term ibrutinib treatment and no new or unexpected AEs were observed.Dose modification (dose reduction or dose hold) was effective in resolving AEs for most patients, likely facilitating continuation of ibrutinib treatment. ",
"section_name": "Conclusions",
"section_num": "5."
}
] | [
{
"section_content": "We thank the patients who participated in the study and their supportive families, as well as the investigators and clinical research staff from the study centers.Editorial support was provided by Melanie Sweetlove, and funded by Pharmacyclics LLC, an AbbVie Company. ",
"section_name": "Acknowledgments:",
"section_num": null
},
{
"section_content": "Funding: This research was funded by Pharmacyclics LLC, an AbbVie Company. The study was conducted according to the guidelines of the Declaration of Helsinki, and was approved by the Institutional Review Boards or Independent Ethics Committees of each participating institution. Informed Consent Statement: Informed consent was obtained from all patients involved in the study. ",
"section_name": "Institutional Review Board Statement:",
"section_num": null
},
{
"section_content": "Funding: This research was funded by Pharmacyclics LLC, an AbbVie Company. ",
"section_name": "",
"section_num": ""
},
{
"section_content": "The study was conducted according to the guidelines of the Declaration of Helsinki, and was approved by the Institutional Review Boards or Independent Ethics Committees of each participating institution. Informed Consent Statement: Informed consent was obtained from all patients involved in the study. ",
"section_name": "Institutional Review Board Statement:",
"section_num": null
},
{
"section_content": "Data Availability Statement: Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. ",
"section_name": "",
"section_num": ""
},
{
"section_content": "The following are available online at https://www.mdpi.com/article/10.3390/cancers15020507/s1: Figure S1, Adverse events of clinical interest of any grade by yearly interval; Figure S2, AEs leading to dose modifications over time in patients on long-term ibrutinib treatment for ≥5 years; Table S1 honoraria from Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; consulting/advisory role and speakers bureau for BeiGene, Gilead, Janssen, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; research funding from AstraZeneca, BeiGene, and Pharmacyclics LLC; an AbbVie Company; travel/accommodations/expenses from Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC; an AbbVie Company.This study was sponsored by Pharmacyclics LLC, an AbbVie Company.The sponsor was involved in study design, data analysis, data interpretation, writing/review of the manuscript, and the decision to publish the results.The sponsor had no role in data collection. ",
"section_name": "Supplementary Materials:",
"section_num": null
}
] |
10.1186/s40364-020-00220-5 | The biological function and clinical significance of SF3B1 mutations in cancer | <jats:title>Abstract</jats:title><jats:p>Spliceosome mutations have become the most interesting mutations detected in human cancer in recent years. The spliceosome, a large, dynamic multimegadalton small nuclear ribonucleoprotein composed of small nuclear RNAs associated with proteins, is responsible for removing introns from precursor mRNA (premRNA) and generating mature, spliced mRNAs. SF3B1 is the largest subunit of the spliceosome factor 3b (SF3B) complex, which is a core component of spliceosomes. Recurrent somatic mutations in <jats:italic>SF3B1</jats:italic> have been detected in human cancers, including hematological malignancies and solid tumors, and indicated to be related to patient prognosis. This review summarizes the research progress of <jats:italic>SF3B1</jats:italic> mutations in cancer, including <jats:italic>SF3B1</jats:italic> mutations in the HEAT domain, the multiple roles and aberrant splicing events of <jats:italic>SF3B1</jats:italic> mutations in the pathogenesis of tumors, and changes in mutated cancer cells regarding sensitivity to SF3B small-molecule inhibitors. In addition, the potential of <jats:italic>SF3B1</jats:italic> or its mutations to serve as biomarkers or therapeutic targets in cancer is discussed. The accumulated knowledge about <jats:italic>SF3B1</jats:italic> mutations in cancer provides critical insight into the integral role the SF3B1 protein plays in mRNA splicing and suggests new targets for anticancer therapy.</jats:p> | [
{
"section_content": "Of the 3.3 billion base pairs of haploid DNA in the human genome, approximately 20,000 protein-coding genes have been identified by the Encyclopedia of DNA Elements (EN-CODE) project [1].However, the number of protein-coding genes is surprisingly low given the proteomic complexity, as the number of protein isoforms expressed from this gene set has been estimated to be at least 5-10-fold higher [2][3][4].The generation of protein diversity is primarily due to the process of precursor mRNA (premRNA) splicing, which is controlled by a complex regulatory system that consists of an enormous number of sequence elements and trans-acting splicing factors; therefore, it is not surprising that the mRNA splicing machinery is susceptible to mutations and that these mutations are implicated in many human diseases, including cancer [5,6].Indeed, genomewide studies have revealed more than 15,000 tumorassociated splice variants in a wide variety of cancers [7,8]. Recently, the most interesting mutations detected in human cancer were found to target components of the spliceosome involved in the mRNA-splicing process, as indicated by genomic DNA analysis of a variety of human tumors studied through the Cancer Genome Project.One of the most exciting discoveries has been recurring somatic mutations in genes encoding 3 splicesite recognition protein components and serine/arginine-rich (SR) splicing factors, which were initially discovered in myelodysplastic syndrome (MDS) in 2011 and later reported in other hematological malignancies, including solid tumors [9][10][11][12][13].Spliceosome mutations in cancers have highlighted the importance of the spliceosome pathway as a direct player in carcinogenesis and led to questions regarding the functional roles and molecular mechanisms of these mutations [14]. In this review, we describe spliceosome-associated transcript processing and its impact on disease.Moreover, we focus on one of the frequently mutated spliceosome proteins: cancer-related splicing factor 3b subunit 1 (SF3B1).We mainly summarize the distribution of mutations in SF3B1, mutant expression in tumors and its prognostic value.In particular, we discuss the functional consequences of SF3B1 mutation in tumors, with multiple roles in tumor pathogenesis, aberrant splicing events, and changes in sensitivity to SF3B smallmolecule inhibitors.The potential value of SF3B1 or its mutation as a novel cancer therapeutic target and marker that is more sensitive to spliceosome inhibitors is also described.Finally, we explore the options available for future research on the biological function and clinical significance of SF3B1 mutations in cancer. ",
"section_name": "Background",
"section_num": null
},
{
"section_content": "Precursor mRNA splicing is an essential step in the posttranscriptional regulation of gene expression and is a process that involves the removal of noncoding sequences (introns) from premRNA and the ligation of coding sequences (exons) to form mRNA. PremRNA splicing is catalyzed by the spliceosome, a complex consisting of 5 small nuclear RNAs (snRNAs) that associate with proteins to form particles termed small nuclear ribonucleoproteins (snRNPs) [15][16][17].To date, two types of spliceosomes with unique compositions have been characterized: U2-dependent (major) spliceosomes and U12-dependent (minor) spliceosomes.The former spliceosome has been found in all eukaryotes and consists of the U1, U2, U5, and U4/U6 snRNPs and numerous proteins.Each U1, U2, and U5 snRNP has a single snRNA and several proteins; the U4 and U6 snRNPs have 2 snRNAs and several proteins.This spliceosome catalyzes the vast majority of transcript splicing events, removing the most commonly encountered class of introns (U2-type introns) (more than 99% in humans) [18,19].In contrast, the U12-dependent spliceosome is found only in a number of organisms, and acts on U12-type introns (less than 1% of introns in humans) [20,21].The difference between U2-type and U12-type introns is in the consensus splicesite sequence.The U12-dependent spliceosome also consists of 5 snRNPs, U11, U12, U5, and U4atac/U6atac snRNPs [22,23]. The stepwise interactions between premRNA and both U2-and U12-dependent spliceosome snRNPs are highly ordered, as shown in Fig. 1.Briefly, assembly of the U2dependent spliceosome is initiated by interaction of the U1 snRNP with the 5′ splice site, which includes a GU, leading to the formation of the E complex.Then, the U2 snRNP binds to the branch site (BS) to generate the A complex or the prespliceosome.When the U5 and U4/ U6 snRNPs interact with the A complex, the B complex is generated.U4/U6 base-pairing interaction is disrupted, and U6 displaces U1 snRNA, which then binds to the 5′ splice site.After B complex rearrangement, a catalytically active B* complex is produced through U1 and U4 snRNP dissociation.The mRNA is released after completion of the first (the C complex is formed) and second catalytic steps of splicing, in which the intron is removed, and the spliceosome dissociates to be recycled Fig. 1 SF3B1 functions in the stepwise assembly of the U2-and U12-dependent spliceosomes.There are two types of spliceosomes: U2dependent spliceosomes (left) and U12-dependent spliceosomes (right).Assembly of the U2-dependent spliceosome consists of 5 snRNPs, U1, U2, U5, and U4/U6 snRNPs; the U12-dependent spliceosome also consists of 5 snRNPs: U11, U12, U5, and U4atac/U6atac snRNPs.The difference between the two spliceosomes is in the consensus splice-site sequences, namely, U2-type or U12-type premRNA introns.SF3B1 is shared in the core components between the two spliceosomes and plays a key role in the recognition and selection of the branch site (BS) by interacting with premRNA in a sequence-independent manner, reinforcing stability during U2 (or U12) snRNA/BS interaction for new premRNA splicing [24,25].Assembly of the U12dependent spliceosome is similar to that of the U2dependent spliceosome because U11, U12 and U4atac/ U6atac snRNPs are functional analogs of the snRNPs U1, U2 and U4/U6.U12-dependent spliceosome assembly also involves sequential formation of the A, B, B*, and C complexes, but the earliest E complex formation step does not occur [21,23].The differences in the premRNA splicing mechanism mediated by the U2-and U12-dependent spliceosomes appear to involve only early intron recognition events and not the catalytic process. A large, diverse and dynamic protein has been found that interacts with snRNAs to form snRNPs within the spliceosome.Although the U2-and U12-dependent spliceosomes differ in their snRNA composition, they share many proteins [26][27][28][29].For example, all of the subunits of the protein complex SF3B, namely, SF3B155/SF3B1, SF3B145, SF3B130, SF3B49, SF3B14a/p14, SF3B14b and SF3B10, are the same [30].SF3B contributes a molecular mass of ~450 kDa to each snRNP, and it has been demonstrated to play a key role in the recognition and selection of the branch site (BS) during splicing by interacting with the premRNA at or near the BS in a sequence-independent manner, reinforcing stability during the U2 snRNA/BS interaction [31].In addition, numerous splicing factors, including an array of regulatory elements and proteins, participate in premRNA splicing events involving the two types of spliceosomes, such as exonic splicing enhancer (ESE), exonic splicing silencer (ESS), intronic splicing enhancer (ISE), intronic splicing silencer (ISS), SR proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), and others [5,17,[32][33][34].Thus, although premRNA splicing is traditionally considered to involve separate and sequential processes, it is difficult for spliceosomes and associated proteins to detect specific splice sites in a vast RNA pool.This complexity makes the premRNA splicing machinery susceptible to sequence polymorphisms and deleterious mutations, some of which eventually lead to diseases, the number of which is growing [5].Therefore, some specific mutations or polymorphisms of premRNA splicing factors have become important diagnostic markers and therapeutic targets in human diseases. ",
"section_name": "Precursor mRNA (premRNA) splicing",
"section_num": null
},
{
"section_content": "Two different modes of splicing have been defined: constitutive splicing and alternative splicing.Constitutive splicing is the process of removing introns from pre-mRNA and joining the exons together to form a mature mRNA sequence.Alternative splicing is the process by which the exons are either retained or targeted for removal in different combinations to yield a diverse array of mRNAs from a single premRNA [35].There are several distinct patterns of alternative splicing, including cassette exons (in which one or more exons are either skipped or included), alternative 5′ splice sites, intron retention, mutually exclusive exons, alternative 3′ splice sites, and complex splicing patterns [36].More than 90% of human genes produce transcripts that are alternatively spliced, and 60% of the splice variants encode distinct protein isoforms with unique cellular functions or properties [37][38][39].Thus, alternative splicing plays important biological roles in the proliferation, differentiation and/or development of cells.In humans, the regulation of alternative splicing is tightly controlled during normal biological events [40].Misregulation of alternative splicing can lead to the production of aberrant protein isoforms, which may contribute to serious diseases, including cancers.Thus, an in-depth investigation of alternative splicing regulation has become the trend to understand the mechanisms of human diseases. ",
"section_name": "Alternative splicing",
"section_num": null
},
{
"section_content": "Disease-related mutations can affect splicing by altering splice site sequences, splicing regulatory sequences, or genes of the splicing machinery itself (i.e., spliceosome mutations) [41,42], and mutations of the splice-site sequences or of the splicing regulatory sequences have been documented in a variety of human diseases.For example, mutations in the splice-site sequences of the HBB (hemoglobin, beta) gene lead to abnormal splicing of HBB and defective synthesis of its protein β-globin in human β + -thalassemia [43][44][45].In human multisystem proteinopathy and amyotrophic lateral sclerosis (ALS), mutations in the prion-like domains of hnRNPA2B1 and hnRNPA1 occur [46].An array of mutations in splicing cis-acting sequences include those of LKB1 (liver kinase B1), KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog), CDH17 (cadherin 17), KLF6 (Kruppel-like factor 6) and BRCA1 (breast cancer gene 1) in many types of cancers [47,48]. In addition to mutations that alter precursor RNA sequence elements that regulate splicing, components of the spliceosome machinery have been shown to be dysregulated in human disease.An example discovered relatively early is that mutations in tri-snRNP (small ribonucleoprotein), a preassembled complex of U4 snRNA hybridized to U6 (U4/U6 or U4atac/U6atac) that also contains U5 (U4/U6 or U5) and associated proteins, can cause an autosomal dominant form of retinitis pigmentosa (adRP) [6,34].Since 2011, recurrent somatic mutations have been identified in a number of spliceosome components in human malignancies through the Cancer Genome Project, such as U2AF1 (U2AF35), SRSF2 (SC35), SF3B1 (SF3B155 or SAP155), and ZRSR2 (URP) [13].These spliceosome component mutations indicates somatic mutations are an important molecular mechanism underlying splicing deregulation in diseases. In this review, we discuss recently discovered examples of disease-linked spliceosome mutations in SF3B1 that are shared in the core comments between the two spliceosomes (Fig. 1). ",
"section_name": "Splicing mutations in human disease",
"section_num": null
},
{
"section_content": "Distribution of mutations in the molecular architecture of SF3B1 SF3B1 (splicing factor 3b subunit 1) is the largest subunit of the SF3B complex and functions by serving as a core component of the U2 snRNP, which is critical for branch site recognition and for the early stages of spliceosome assembly [49].Structurally, the N-terminal hydrophilic region of SF3B1 has multiple U2AF2 binding motifs [50,51], which may facilitate localization of the U2 snRNP to the vicinity of the branch site.Two-thirds of the C-terminus consists of 22 nonidentical HEAT (Huntingtin, elongation factor 3, subunit An of protein phosphatase 2A, and phosphatidylinositol 3-kinase (PI3K) target of rapamycin 1) repeats, which form rodlike helical structures, providing major scaffolding for the U2 snRNP to support interactions with other SF3B subunits, including p14 [52].The HEAT-repeat superhelix of SF3B1 defines a composite RNA-binding platform for BS recognition.In human diseases, almost all mutations in SF3B1 are located in the HEAT domain, particularly from H4-H12, as shown in Fig. 2.Among the mutated codons, 700 account for more than 50% of the variants observed, and additional codons (666, 662, 622, and 625) have been found to be hotspots for mutation [41,[53][54][55]. ",
"section_name": "SF3B1 mutations in cancer",
"section_num": null
},
{
"section_content": "Mutations in SF3B1 have been implicated as common drivers of hematologic malignancies.Somatic SF3B1 mutations are found in approximately 30% of patients with MDS and as many as 80% of patients with the MDS subtype characterized by ring sideroblasts (MDS-RARS) [41,56,57].These mutations are also present in 20% of patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) [41] and in 15% of patients with chronic myeloid leukemia (CLL) [58][59][60].More recently, SF3B1 mutations have been identified at relatively high frequency in some solid tumors, such as various pigmented tumors, including uveal melanoma (UM) [61,62], mucosal melanoma [63], leptomeningeal melanoma [64] and blue nevus-like cutaneous melanoma [65], and neuroblastomas that arise following chromothripsis [66], estrogen receptor-positive breast cancers (BC) [67], pancreatic ductal adenocarcinoma [68], prostate cancer [69], prolactinomas [70], acute myeloid leukemia [71,72], and many others [73][74][75]. ",
"section_name": "Mutant SF3B1 expression in cancer",
"section_num": null
},
{
"section_content": "The prognostic value of the SF3B1 mutation in MDS remains controversial.Most studies have claimed that patients carrying an SF3B1 mutation have a significantly better overall survival and a lower likelihood of their disease transforming into acute leukemia compared with patients without SF3B1 mutations [11,41,76,77].In contrast, some studies found no significant effect of mutation on clinical outcomes [78,79].Regardless, SF3B1 appears to be the only gene for which somatic mutations are associated with a good prognosis in MDS [41,80].As with MDS, SF3B1 mutations were found to confer a favorable prognosis in uveal melanoma (UM), with a younger age of onset and concurrent disomy 3 [81,82].In addition, patients with SF3B1-mutated UM had better survival (at 5 years) than did SF3B1 wild-type patients.Nonetheless, evidence also shows that the survival differences between patients with SF3B1-mutant tumors and SF3B1 wild-type tumors are not significant over time, as indicated by follow-up data (at 10 years).Moreover, SF3B1-mutant UM is reported to cause late metastasis (median 8.2 years after initial diagnosis), suggesting that patients with SF3B1 mutations are also at risk for metastasis, particularly late-onset metastasis [83].It was inferred that the positive prognostic value of SF3B1 mutation may be partly or completely lost after the acquisition of other gene mutations associated with disease progression [41].In contrast to those in MDS or UM, SF3B1 mutations that are cancer-related occur more commonly in advanced disease and tend to be associated with poor prognosis in other malignancies, including CLL.Thus, the prognostic relevance of SF3B1 mutations in disease may be dependent on cellular contexts. ",
"section_name": "Prognostic value of SF3B1 mutation in cancer",
"section_num": null
},
{
"section_content": "",
"section_name": "Functional consequences of SF3B1 mutation in cancer",
"section_num": null
},
{
"section_content": "To date, it remains unclear what functional role SF3B1 mutations play in carcinogenesis, and it has not been well established whether deregulated SF3B1 activity is required for the maintenance of cancer [84].To address these questions, the role of SF3B1 mutations in malignant hematopoiesis has been investigated in vitro and in vivo.Regarding MDS, an SF3B1 K700E conditional knock-in mouse has been generated [85], and heterozygous expression of SF3B1 K700E caused progressive macrocytic anemia [85].Moreover, SF3B1 K700E expression was associated with aberrant 3′ splice-site selection as well as increased nonsense-mediated decay [85].In another study, conditional SF3B1 flox-K700E/+ mice were generated by targeted modification of the SF3B1 locus in JM8 mouse embryonic stem cells (ESCs).SF3B1 K700E/+ mice develop progressive normocytic anemia without ring sideroblasts [86].In addition to erythropoiesis, SF3B1 K700E/+ mice had reduced numbers of hematopoietic stem cells (HSCs) and exhibited a myeloid cell bias [86].Furthermore, the self-renewal potential of SF3B1 K700E/+ HSCs was determined by their repopulating ability in competitive transplantation assays into either young or old recipient mice.The results revealed a fitness disadvantage of mutant over wild-type HSCs [86], which contrasts with observations that mutant SF3B1 drives clonal hematopoiesis and may even be the sole identifiable driver mutation in human MDS [87,88].In addition, simultaneous expression of SF3B1 and SRSF2 mutations in mice resulted in increased apoptosis and reduced quiescence of hematopoietic stem progenitor cells (HSPCs).Moreover, combined expression of SF3B1 and SRSF2 mutations impaired expression of regulators of HSPC survival and increased sensitivity to inflammatory stimulation [89].In human SF3B1-mutated CLL cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was found to be increased at baseline and upon irradiation, demonstrating that mutations in SF3B1 are associated with increased DNA damage and/or an aberrant response to DNA damage [90].In many cancer cells, SF3B1 mutation was found to dysregulate multiple cellular functions, including heme biosynthesis, immune infiltration, DNA damage response, R-loop formation, telomere maintenance, and Notch signaling [74,[91][92][93], as well as many cellular pathways, such as the mitochondrial, Notch and NF-κB pathways [91].These results suggest that SF3B1 mutations play multiple roles in the pathogenesis of tumors. ",
"section_name": "Multiple roles in tumor pathogenesis",
"section_num": null
},
{
"section_content": "In terms of SF3B1 as a core component of splicing machinery, it has been clearly proven that common and tumor-specific splicing aberrations are induced by SF3B1 mutations, and aberrant 3′ ss selection has been established as the most frequent splicing defect [94], with increased alternative 3′ splice site usage [85] and usage of cryptic 3′ splice sites [86], as shown in Fig. 3. Strikingly, SF3B1 variants utilize a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3′ ss to enable aberrant splicing during the second step [94].SF3B1 mutations result in neomorphic activity, causing hundreds of alterations both through aberrant splicing and dysregulated gene expression in common alternative splicing signatures in different types of cancers [95].Furthermore, SF3B1 mutations are linked to various RNA processing mechanisms, such as alternative terminal exons, alternative 3′ acceptor splice sites, alternative cassette exons, alternative first exon, alternative branch point usage, and intron retention [96,97].Approximately 50% of aberrantly spliced mRNAs are subjected to nonsense-mediated decay, resulting in downregulation of gene and protein expression [94,98].However, few of these genes have been functionally implicated in driving the diseases known to be associated with SF3B1 mutations, including the genes shown in Fig. 4. Thus, the functional consequences and mechanisms of SF3B1 mutations in cancers need to be further investigated. ",
"section_name": "Aberrant splicing events",
"section_num": null
},
{
"section_content": "Fifteen aberrant splicing (PARVG, RPRD1A, DOM3Z, CXXC1, AP1G2, SNRPN, TCEA2, NICN1, ABCC5, ERCC3, SNRPN, PPOX, GPR108, PSTPIP1, NICN1) events have been correlated with clinical variables that showed a significant difference between SF3B1 mut and SF3B1 wt patients with MDS, including a lower percentage of bone marrow (BM) blasts and higher number of white blood cells, absolute neutrophil count (ANC), and platelet count (Plt) in the SF3B1 mut group [92].Moreover, isoform expression of extracellular exosome/focal adhesion genes (CRTC2, PPOX, AHSA2, DHP5) produced by aberrant splicing events in SF3B1 mut patients has been identified as a significant survival predictor in MDS [92,99].The functions of eight genes (BRD9, SUGP1, MAP3K7, TERC, KLF8, DVL2, SEPT2, and ABCB7) with deregulated expression due to SF3B1 mutations in tumors are discussed below. ",
"section_name": "Associations between aberrant splicing and clinical variables or patient survival",
"section_num": null
},
{
"section_content": "Homo sapiens bromodomain containing (BRD) 9 is a core component of the recently described mammalian BRG1-associated factor (BAF) chromatin remodeling complex that plays an important role in maintaining the transcriptional network of pluripotency [100].Previous studies have reported that BRD9 is required for the survival of some cancer types, particularly cancers with mutations that affect polybromo-associated BAF and canonical BAF6 [101][102][103].Recently, it was found that total levels of BRD9 mRNA were reduced in patients with CLL, MDS and UM carrying SF3B1 mutation.Further study found that mutant SF3B1 suppressed levels of full-length BRD9 protein without generating a truncated BRD9 protein in UM (MEL270) or myeloid leukemia (K562) cells that express SF3B1 K700E .Mutant SF3B1 recognizes an aberrant, deep intronic branch point within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element, causing subsequent degradation of BRD9 mRNA.Depletion of BRD9 in turn causes loss of noncanonical BAF at CTCF-associated loci, resulting in alteration of BAF localization to chromatin.BRD9 loss may also alter the expression of distinct genes involved in apoptosis and cell growth, adhesion and migration.In addition, it was also found that disruption of ncBAFdependent regulation of HTRA1 (HtrA serine peptidase 1) contributes to the protumorigenic effects of BRD9 loss.Correcting misspliced BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumor growth [100].These results implicate the disruption of noncanonical BAF in the diverse cancer types associated with SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies [104]. ",
"section_name": "BRD9",
"section_num": null
},
{
"section_content": "SUGP1 (SURP And G-patch domain-containing protein, a member of the SURP family of splicing factors that likely interact with SF1 and RNA helicases) is also greatly reduced in samples from MDS patient harboring SF3B1 mutation [53,[105][106][107].Furthermore, loss or weakening of the interaction of SUGP1 with SF3B1 in the spliceosome was found to be the sole cause of defects in BP recognition, which results in the use of cryptic 3′ ss typically located 10-30 nt upstream of canonical 3′ ss [53].That is, under normal conditions, the WT SF3B1 spliceosome uses a canonical BP and 30'ss for splicing; when the interaction between SF3B1 and SUGP1 is disrupted by SF3B1 mutations, the mutant SF3B1 spliceosome uses an upstream BP and a cryptic 30′ ss for splicing.Furthermore, SUGP1 can associate with the mutant spliceosome and partially rescue splicing defects [53].These data suggest that loss of SUGP1 is a common defect in spliceosomes with cancerassociated SF3B1 mutations and that the mutant spliceosome is \"repairable\" in principle via restoration of SUGP1 assembly [108]. ",
"section_name": "SUGP1",
"section_num": null
},
{
"section_content": "MAP3K7 (mitogen-activated protein kinase kinase kinase 7) encodes a kinase that mediates tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and Toll-like receptor signaling through the NF-κB, JNK, and MAPK pathways.Loss of MAP3K7 results in the attenuation or promotion of inflammation, depending on the cellular context [109][110][111].Reduced MAP3K7 mRNA and protein are both found in isogenic cell lines and primary myeloid and lymphoid cells from MDS and CLL patients carrying SF3B1 mutations [89].In contrast, hyperactive NF-κB signaling with increasing p-p65 levels is detected in SF3B1 K700E human myeloid and lymphoid leukemia cells stimulated with LPS.Re-expression of MAP3K7 in SF3B1 K700E cells leads to a significant decrease in p-p65 in both the resting state and following LPS exposure.Additionally, restoration of MAP3K7 expression in SF3B1 K700E cells results in partial rescue of cell clonogenicity [89].These data suggest that SF3B1 mutations affect the splicing of MAP3K7, which, at least in part, the results in hyperactivation of NF-κB signaling, which is associated with MDS pathogenesis.TERC TERC (telomerase RNA component), encoding an essential RNA component of telomeres, plays a role in cell proliferative potential, telomerase activity and telomere length, and TERC mutations have been found in autosomal dominant dyskeratosis congenita (DC), aplastic anemia, MDS, and cervical cancer [112][113][114][115]. TERC is a noteworthy target with significantly increased expression in SF3B1-mutated CLL samples, as based on amplification using total RNA [91].Upregulation of TERC and TERT (telomerase reverse transcriptase) was confirmed in Nalm6 isogenic cell lines with K700E and H622Q mutations.Not surprisingly, higher telomerase activity was detected in Nalm-6 SF3B1 K700E cells than in wild-type cell lines.These data suggest that mutant SF3B1 may affect telomerase activity through dysregulation of TERC and TERT expression [91]. ",
"section_name": "MAP3K7",
"section_num": null
},
{
"section_content": "KLF8 (Kruppel-like transcription factor 8) has been found to be involved in tumor cell proliferation, transformation, and progression and in DNA damage repair in several different tumors, including renal cell carcinoma, hepatocellular carcinoma and breast cancer [116].KLF8 is consistently upregulated in SF3B1-mutated CLL samples at both single-cell and bulk RNA levels.Overexpression of SF3B1 in cells induces phosphorylation of H2AX (γH2AX) [90,91] and CHK2 (checkpoint kinase 2) [91], two markers of DNA damage, following exposure to gamma irradiation.These data demonstrate that single mutations in SF3B1 are associated with increased DNA damage and/or an aberrant response to damage and that SF3B1 mutation-associated gene dysregulation is a contributor to altered DNA responses [90,91]. ",
"section_name": "KLF8",
"section_num": null
},
{
"section_content": "Dishevelled 2 (DVL2) has been previously reported to play a role in both canonical and noncanonical Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and inducing transduction of the Wnt signal to downstream effectors [117,118].Relatively high expression of the DVL2 splice variant and the protein product of altered DVL2 have been confirmed in individual primary CLL cells with SF3B1 mutation [91].Interestingly, altering DVL2 does not influence Wnt signaling, but it does affect the Notch pathway: expression of altered DVL2 markedly abrogates the activation of Notch1 and expression of the Notch pathway target gene HES1 (hairy and enhancer of split-1).Moreover, combined expression of WT and altered DVL2 reverses these suppressive effects, suggesting a dominant impact of altered DVL2 on the WT isoform [91].These data implicate DVL2 as a target of mutated SF3B1 through which alternative splicing modulates Notch signaling activity. ",
"section_name": "DVL2",
"section_num": null
},
{
"section_content": "SEPT2 (septin 2), a member of the septin family of guanosine triphosphatases, plays a role in the biogenesis of polarized columnar-shaped epithelium by maintaining polyglutamylated microtubules and an important role in the regulation of mitosis and cell growth [119,120].SEPT2 is significantly downregulated in CD34 + cells with SF3B1 mutations in patients with MDS [92].In addition, the effect of SEPT2 silencing on erythroid cell growth and differentiation has been studied in human BM CD34 + cells.It was found that SEPT2 silencing leads to significantly impaired growth, G1/S transition arrest and a significant decrease in intermediate and late erythroid cell populations [92].These results suggest that aberrant splicing of SEPT2 may lead to impaired erythropoiesis in association with SF3B1 mutations in patients with MDS. ",
"section_name": "SEPT2",
"section_num": null
},
{
"section_content": "ABCB7 (ATP binding cassette subfamily B member 7) encodes a half-transporter involved in the transport of heme from the mitochondria to the cytosol and plays a role in mitochondrial iron accumulation, isodicentric chromosome formation (X)(q13) and sideroblastic anemia, which is involved in many hematologic malignancies [121][122][123].Aberrant splicing of ABCB7 occurs in MDS RARS and SF3B1 mut MDS patients and significant ABCB7 downregulation in SF3B1 mut cases [92,96].In normal bone marrow, ABCB7 downregulation reduces erythroid differentiation, growth and colony formation and results in a gene expression pattern similar to that observed in intermediate MDS-RARS erythroblasts and in the accumulation of FTMT.Moreover, silencing SF3B1 results in downregulation of ABCB7 in K562 cells undergoing erythroid differentiation, implicating ABCB7 in the acquisition of the RARS phenotype [124].Furthermore, an ABCB7 cryptic 3′ splice site event was detected in SF3B1-mutant HSCs carrying the SF3B1 K700E mutation; nonsense-mediated RNA decay (NMD) can target the aberrantly spliced ABCB7 transcript and underlies the downregulation of ABCB7 observed in MDS patients with SF3B1 mutation.Moreover, treatment of SF3B1 K700E -mutant cells with cycloheximide resulted in an increase in the aberrantly spliced form of the ABCB7 transcript [96].Interestingly, the sequence of the ABCB7 cryptic ss is not conserved in mice, and there is no aberrant splicing of ABCB7 in SF3B1-mutant murine cells [85,86], which indicates significant differences in the transcripts affected because of SF3B1 K700E between humans and mice.These data provide strong evidence that SF3B1 mutation leads to aberrant ABCB7 splicing and downregulation via NMD in human cancer cells and suggest an ABCB7-based therapeutic approach for treating these malignancies. In addition, the roles and mechanisms of many other key cancer-related genes that have been detected by RNA sequencing and validated by qRT-PCR in distinct types of cancer need to be further investigated, such as TMEM14C (transmembrane protein 14C), SEPT6 (septin 6), and ENOSF1 (enolase superfamily member 1), as shown in Fig. 4.More genes that can be categorized into one of two large groups, a cell-autonomous gene set and a set of genes in immune cells with signatures related to immune cell infiltration, need to be confirmed in vitro and in vivo [74]. ",
"section_name": "ABCB7",
"section_num": null
},
{
"section_content": "Because the spliceosome SF3B complex has emerged as a potential therapeutic target, SF3B small-molecule inhibitors are currently under development and have entered clinical trials [125][126][127].These inhibitors specifically target the SF3B protein complex, leading to the loss of spliceosome function with regard to 3 splice site recognition and resulting in aberrant alternative splicing/mRNA transport.Among them, three bacterial fermentation products (FR901464, herboxidiene, and pladienolide) were identified as natural compounds with antitumorigenic properties [126].In addition to natural drugs, meayamycin, E7107, and spliceostatin A (SSA) have been developed as synthetic analogs with improved stability and solubility [58].Among them, pladienolide (Pla) stalls SF3B in an open conformation by acting like a wedge within a hinge, modulating the transition of SF3B to the closed conformation to form the adenosine-binding pocket and stably accommodate the BS/U2 duplex [128,129].Although Pla-B might be located in the vicinity of both SF3B1 and SF3B3, it only binds to SF3B3 [130].Additionally, E7107, a synthetic derivative of pladienolide D, and SSA, a methylated derivative antitumor natural product FR901464, mainly destabilize U2 snRNP assembly at 3′ splice sites by blocking SF3B from binding to RNA [126].E7107 targets SF3B1 to block ATP-dependent A complex formation as well as a conformational change in U2 that exposes the snRNA region responsible for base pairing to the branchpoint sequence [131], whereas SSA induces a conformational shift in the U2 snRNP to bind to \"decoy\" sequences that can occur upstream of the branchpoint sequence [58]. Interestingly, one disease-associated SF3B1 mutation has the opposite effects on sensitivity to SF3B smallmolecule inhibitors, as shown in Fig. 5.An R1074H mutation in SF3B1 confers resistance to pladienolide activity by impairing the ability of pladienolide B to bind to SF3B due to the physical interference caused by SF3B1 mutation [132], and it was speculated that SF3B1 mutations in other HEAT repeats might have the same effect [58].These data indicate that the mutant SF3B1 protein has an impaired response to pladienolide B. In contrast to pladienolide B, it was reported that the SF3B1 mutant cell lines Panc 05.04 (pancreatic, K700E) and ESS-1 (endometrial, K666N) were more sensitive to SAA, leading to inhibition of cell growth [133].In contrast to SF3B1 +/+ murine HSPCs, SF3B1 +/K700E HSPCs were more sensitive to the spliceosome modulator E7107E [85].Furthermore, treatment of SF3B1 +/K700E recipients with E7107 in vivo caused a significant decrease in CD45.2 chimerism in the peripheral blood, bone marrow, and spleen [85].These data demonstrate that SF3B1 mutation enhances the sensitivity of tumor cells to the spliceosome modulator E7107 and SAA but not pladienolide B. SF3B1 mutation therefore sensitizes cells to pharmacologic targeting of wild-type SF3B1, consistent with the observation that the growth of SF3B1-mutant endometrial cancer and uveal melanoma cell lines was impaired by deletion of wild-type, but not mutant, SF3B1 [84].Although the mechanism of the enhancement sensitivity to splicing inhibitors is unknown, probably because a mutated SF3B1 gene may be unable to tolerate further perturbations in splicing and therefore be preferentially sensitive to pharmacological splicing inhibition [134], these findings suggest that there may be a therapeutic window for the use of spliceosome modulators in the treatment of hematologic malignancies with SF3B1 mutation [85].Overall, mutated SF3B1 has been detected in hematological malignancies and tumors and has been proven to be related to patient prognosis, transcription, alternative splicing, and sensitivity to SF3B small-molecule inhibitors.However, only a few genes affected by SF3B1 mutation have been extensively studied to date, and the roles and mechanisms of these genes still need to be confirmed. ",
"section_name": "Changes in sensitivity to SF3B small-molecule inhibitors",
"section_num": null
},
{
"section_content": "Primary tumors with SF3B1 mutations display alternative splicing in select key genes in cancer, including CLL, MDS, and uveal melanoma; this signature is conserved between cancer sites and is independent of the mutant amino acid [95], which implies that SF3B1 mutations may represent an important clinical significance in tumors.Indeed, SF3B1 is the most commonly mutated spliceosomal component gene in breast cancer, and mutations affecting this gene are significantly associated with ER-positive disease [67].Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3B complex inhibitor spliceostatin A, and treatment resulted in perturbation of the splicing signature [67].Thus, given the multiple roles in the pathogenesis of tumors and splicing events induced by SF3B1 mutations in cancer, as well as the potentially increased sensitivity of cancers to some SF3B small-molecule inhibitors, SF3B1 or its mutation may represent a prognostic biomarker and therapeutic target for cancer, and pharmacological modulation of splicing may represent an important therapeutic strategy [134].For example, although SF3B1 mutations occur at a low frequency (1.1%) in prostate cancer (PCa) [69], SF3B1 mRNA and protein levels are higher in tumor glands than in nontumor adjacent regions [135].Notably, SF3B1 expression correlated positively with clinical and molecular features, including Gleason score and vascular and perineural invasion.Pharmacological blockade of SF3B1 with pladienolide-B reduced malignant features of PCa cells and modulated key signaling pathways, malignancy markers, and expression of oncogenic splicing variants AR-v7 and In1-ghrelin, spliceosome components and splicing factors as well as expression of EJC and SURF components and NMD factors [135].That is, dysregulation of SF3B1 expression may be involved in the development, progression, and aggressiveness of PCa, and SF3B1 might represent a new prognostic biomarker and therapeutic target in this devastating pathology.These results also indicate that SF3B1 inhibition leads to a decrease in the aggressiveness features of PCa cells through both direct and indirect mechanisms, possibly involving the modulation of different types of cellular stress processes.As SF3B1 variants exhibit an impaired response to pladienolide B [132], other inhibitors, such as E7107E and SSA, may have better antitumor activity for PCa.The prognostic and therapeutic potential of SF3B1 in other types of cancer needs to be further studied. ",
"section_name": "SF3B1 or its mutation as a novel therapeutic target in cancer",
"section_num": null
},
{
"section_content": "In eukaryotes, the RNA splicing system, as essential cellular machinery, is critical for successful transcription through constitutive splicing and guarantees the functional diversity of protein products through alternative splicing.Thus, deregulation of this machinery causes severe developmental abnormalities [42,92,136].Recent studies have shown that mutations in the RNA splicing machinery significantly affect the RNA splicing system by altering many splicing patterns associated with 3′ splice sites, suggesting that aberrant splicing patterns induced by spliceosome mutations are directly linked to disease phenotypes [13].SF3B1 is a shared core component of snRNPs both in major and minor spliceosomes and plays a critical role in the early and later stages of spliceosome assembly.SF3B1 mutations occur in many types of tumor and play an important role in the development and progression of cancer.However, the functional impact and mechanisms of the SF3B1 mutationderegulated splicing pattern on oncogenesis need to be better understood.In addition, although it has become clear that aberrant premRNA alternative splicing is a major contributor to cancer phenotypes, studies on the misregulation of alternative splicing induced by SF3B1 mutation in cancer have not kept pace with the latest data.Moreover, mutant SF3B1 may have a distinct function not only in the direct regulation of RNA splicing but also in the elongation and stability of DNA, which may be important for the acquisition of specific disease phenotypes [36].Further work is also required to evaluate the molecular mechanism by which mutations in SF3B1 HEAT domains may influence the base-pairing potential of U2 snRNA [14].Future clinical work is also needed to explore the relationship between SF3B1 mutations and mutations in other cancer-related genes, including those of other spliceosome-associated proteins, splicing regulatory factors, and transcriptional factors.Moreover, a valuable tool for dissecting the effects of SF3B1 mutations on the transformation, splicing, and functions of SF3B1 was established in a mouse model [87,88], and investigation of the role of the yeast ortholog Hsh155 supports a novel mechanism in which SF3B1 helps to define the BS during premRNA splicing [137].These findings are part of wide ongoing effort to generate genetically engineered model systems to study the biological and biochemical consequences of spliceosomal mutations in model systems as diverse as yeast, zebrafish, mouse, and human cells [138].Finally, as the effects of splicing-modulation strategies targeting SF3B1 mutations are currently unpredictable, laboratory, preclinical and clinical studies are required understand the biological and clinical significance of SF3B1 mutations in cancer. ",
"section_name": "Conclusions and future perspectives",
"section_num": null
}
] | [
{
"section_content": "Not applicable. ",
"section_name": "Acknowledgments",
"section_num": null
},
{
"section_content": "This study was supported by the Qingdao Source Innovation Program (18-2-2-76-jch), the National Natural Science Foundation of China (91849209, 31671447), and the Innovative Talent Program of Qingdao (18-1-2-6-zhc). ",
"section_name": "Funding",
"section_num": null
},
{
"section_content": "Not applicable, all information in this review can be found in the reference list. ",
"section_name": "Availability of data and materials",
"section_num": null
},
{
"section_content": "Abbreviations ABCB7: ATP-binding cassette subfamily B member 7; adRP: Autosomal dominant retinitis pigmentosa; ALS: Amyotrophic lateral sclerosis; BC: Breast cancer; BRD9: Homo sapiens bromodomain containing 9; BS: Branch site; CLL: Chronic myeloid leukemia; ENOSF1: Enolase superfamily member 1; ESE: Exonic splicing enhancer; ESS: Exonic splicing silencer; HSC: Hematopoietic stem cells; HSPC: Hematopoietic stem progenitor cell; hnRNP: Heterogeneous nuclear ribonucleoprotein; ISE: Intronic splicing enhancer; ISS: Intronic splicing silencer; KLF8: Kruppel-like transcription factor 8; MAP 3 K7: Mitogen-activated protein kinase kinase kinase 7; MDS: Myelodysplastic syndrome; snRNA: Small nuclear RNA; snRNP: Small nuclear ribonucleoprotein; SRSF2: Serine/arginine-rich splicing factor 2; SF3B1: Splicing factor 3b subunit 1; SURP1: SURP and G-Patch domain containing 1; TERC: Telomerase RNA component; TERT: Telomerase reverse transcriptase; TMEM14C: Transmembrane protein 14C; U2AF1: U2 small nuclear RNA auxiliary factor 1; UM: Uveal melanoma; ZRSR2: CCCH type zinc finger, RNA binding motif and serine/arginine rich protein 2 All authors contributed to the literature search and writing of the manuscript.All authors read and approved the final manuscript. No ethics approval was required for this review that did not involve patients or patient data. All authors consent to publication. The authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ",
"section_name": "Authors' contributions",
"section_num": null
},
{
"section_content": "Abbreviations ABCB7: ATP-binding cassette subfamily B member 7; adRP: Autosomal dominant retinitis pigmentosa; ALS: Amyotrophic lateral sclerosis; BC: Breast cancer; BRD9: Homo sapiens bromodomain containing 9; BS: Branch site; CLL: Chronic myeloid leukemia; ENOSF1: Enolase superfamily member 1; ESE: Exonic splicing enhancer; ESS: Exonic splicing silencer; HSC: Hematopoietic stem cells; HSPC: Hematopoietic stem progenitor cell; hnRNP: Heterogeneous nuclear ribonucleoprotein; ISE: Intronic splicing enhancer; ISS: Intronic splicing silencer; KLF8: Kruppel-like transcription factor 8; MAP 3 K7: Mitogen-activated protein kinase kinase kinase 7; MDS: Myelodysplastic syndrome; snRNA: Small nuclear RNA; snRNP: Small nuclear ribonucleoprotein; SRSF2: Serine/arginine-rich splicing factor 2; SF3B1: Splicing factor 3b subunit 1; SURP1: SURP and G-Patch domain containing 1; TERC: Telomerase RNA component; TERT: Telomerase reverse transcriptase; TMEM14C: Transmembrane protein 14C; U2AF1: U2 small nuclear RNA auxiliary factor 1; UM: Uveal melanoma; ZRSR2: CCCH type zinc finger, RNA binding motif and serine/arginine rich protein 2 ",
"section_name": "",
"section_num": ""
},
{
"section_content": "All authors contributed to the literature search and writing of the manuscript.All authors read and approved the final manuscript. ",
"section_name": "Authors' contributions",
"section_num": null
},
{
"section_content": "No ethics approval was required for this review that did not involve patients or patient data. ",
"section_name": "Ethics approval and consent to participate",
"section_num": null
},
{
"section_content": "All authors consent to publication. ",
"section_name": "Consent for publication",
"section_num": null
},
{
"section_content": "The authors declare that they have no competing interests. ",
"section_name": "Competing interests",
"section_num": null
},
{
"section_content": "Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ",
"section_name": "Publisher's Note",
"section_num": null
}
] |
10.21320/2500-2139-2020-13-4-366-381 | Mantle Cell Lymphoma: History, Current Principles of Diagnosis, and Treatment (Literature Review) | <jats:p>Mantle cell lymphoma (MCL) is a heterogeneous disease with a broad spectrum of clinical manifestations from rare indolent cases requiring no immediate treatment to aggressive fast-proliferating tumors. Differences in clinical behavior are rooted in molecular grounds which in the latest edition of WHO hematopoietic and lymphoid tissue tumor classification formed the basis for dividing MCL into two variants: classical (in most cases) and indolent. In last decades, our insight into biology and disease development mechanisms has been considerably enhanced. Further, it will help to risk stratify patients not only according to clinical factors (MIPI) but also taking into account molecular and biological properties of tumor (Ki-67 proliferation index, ТР53, NOTCH1, and NOTCH2 mutations, complex karyotype, and unmutated IGHV status). Treatment algorithms based on intensive chemotherapy with high-dose cytarabine and autologous hematopoietic stem cell transplantation with further rituxi-mab maintenance therapy ensure long-term monitoring of the disease in many MCL patients. The use of new “chemo-free” regimens and rational combinations (bortezomib, BTK inhibitors, lenalidomide, and venetoclax) offers the hope of a departure from conventional chemotherapy for a certain part of patients. Novel drugs with unique modes of action enabled, to some extent, to deconstruct the stigma of MCL fatality.</jats:p> | [
{
"section_content": "Для цитирования: Тумян Г.С.Мантийноклеточная лимфома: история, современные принципы диагностики, лечение (обзор литературы).Клиническая онкогематология.2020;13(4):366-81.DOI: 10.21320/2500-2139-2020-13-4-366-381 For citation: Tumyan GS.Mantle Cell Lymphoma: History, Current Principles of Diagnosis, and Treatment (Literature Review).Cl inical oncohematology.2020;13(4):366-81.(In Russ ).DOI: 10.21320/2500-2139-2020-13-4-366-381 ",
"section_name": "Мантийноклеточная лимфома",
"section_num": null
},
{
"section_content": "Современная история МКЛ начинается с классификации лимфом Генри Раппапорта, опубликованной в журнале «Cancer» в 1954 г. [1].Она основана на морфологическом описании клеточного состава и определении характера роста опухоли (нодулярный и диффузный).К этому времени отсутствовало понимание феномена «бласт-трансформации» и была принята концепция, что крупные клетки в опухолевой ткани имеют нелимфоидное происхождение и являются потомками стромальных (ретикулярных) клеток лимфатического узла.Было выделено пять типов лимфом: лимфоцитарная (хорошо дифференцированная), лимфоцитарная (мало дифференцированная, лимфобластная), смешанная (лимфоцитарная и ретикулярная), ретикулярная, типа Ходжкина.Эта классификация нашла широкое распространение в США. В течение последующего десятилетия в медицинской науке произошла настоящая революция, которая, безусловно, перевернула все ранее существующие понятия в иммунологии и онкогематологии.Стало очевидным, что лимфоциты представляют собой гетерогенную группу клеток, которые имеют разное линейное происхождение (Т-, В-, NK-) и выполняют разные функции.Лимфомы стали рассматриваться как опухоли иммунной системы, а лимфоцит перестал восприниматься как конечный продукт дифференцировки лимфоидных клеток.Было показано, что под влиянием различных факторов (митогенов или антигенов) лимфоидные клетки могут трансформироваться в крупные пролиферирующие клетки, ранее называвшиеся ретикулярными.Все эти знания легли в основу создания Кильской классификации, предложенной К. Леннертом и представителями его школы [2].В новой классификации наряду с морфологическими особенностями учитывали иммунофенотип клеток лимфоидной опухоли и их соответствие нормальным лимфоцитам разных этапов В-и Т-клеточной дифференцировки.Так появилось новое понятие «неопухолевого эквивалента» (postulated normal counterpart).Уже в Кильской классификации было определено, что большинство лимфом происходит из В-клеток зародышевого (герминативного) центра вторичного лимфоидного фолликула.В зависимости от морфологии и характера течения заболевания было предложено разделять лимфомы на опухоли низкой (мелкие клетки) и высокой (преимущественно бластные элементы) степени злокачественности. К этому времени возможности стадирования и лечения лимфом стали расширяться и возникла большая необходимость в проведении многоцентровых клинических исследований.Путаница в систематизации опухолей делала невозможным сопоставление полученных результатов и тормозила дальнейшие научные изыскания.В Европе повсеместно использовалась Кильская классификация, которая плохо стыковалась с классификацией Г. Раппапорта, принятой патологами и клиницистами в США.По инициативе Национального института рака в 1982 г. публикуется «Рабочая схема» для клинического применения (Working Formulation, WF).По сути это «рабочая платформа», целью которой было совместить уже существующие классификационные системы для совместной работы патологов и клиницистов [3].В этом руководстве учитывается степень злокачественности опухоли и характер ее роста, но не принимаются во внимание данные иммунофенотипа клеток.Несмотря на некоторую полезность WF, желаемая цель не была достигнута, поскольку в Европе продолжают использовать Кильскую классификацию, а отсутствие иммунологической составляющей в WF делает ее нежизнеспособной и бесперспективной. В 1991 г.Peter Isaacson и Harald Stein создали Международную группу по изучению лимфом (ILSG), которая объединила европейских и американских гематопатологов для попытки систематизации опухолей лимфоидной природы с учетом современных понятий.К тому времени уже были внедрены в практику иммуногистохимические методы обработки парафиновых блоков, разработаны новые методики (полимеразная цепная реакция [ПЦР] и флюоресцентная гибридизация in situ [FISH]), которые позволяли провести генетические анализы на криостатных срезах, что значительно облегчило тестирование образцов рутинной биопсии.В качестве маркера определения клональности и линейной принадлежности опухоли изучались перестройки генов, кодирующих синтез В-и Т-клеточных рецепторов.Стало возможным определение соматических гипермутаций в генах, кодирующих синтез вариабельных участков тяжелых цепей иммуноглобулинов (IGHV), что позволило не только говорить о линейной принадлежности опухоли, но и о стадии ее дифференцировки (герминальная, постгерминальная). Именно в это время Международная группа представила консенсусный отчет по определению новой самостоятельной нозологической единицы, которую назвали мантийноклеточной лимфомой (МКЛ) [4].Установлено, что внутри большой группы лимфом низкой степени злокачественности можно выделить особый вариант, который на тот момент определялся как лимфоцитарная лимфома с промежуточной дифференцировкой (lymphocytic lymphoma of intermediate differentiation), либо лимфома из клеток мантийной зоны (mantle zone lymphoma), либо центроцитарная лимфома (centrocytic lymphoma) согласно Кильской классификации.При этом В-клеточном варианте опу- Понимание молекулярных механизмов развития любой опухоли -это, как правило, более поздний этап изучения болезни, который следует после описания ее морфологических, иммунофенотипических и клинических особенностей.В этом контексте не является исключением и МКЛ, при которой подробные патоморфологические и клинические характеристики опухоли предшествовали распознаванию ключевого гена CCND1, критичного в патогенезе этой болезни.Как только стали понятны механизмы становления заболевания, был получен широкий доступ к новым диагностическим инструментам (например, определение циклина D1), которые помогают в дифференциальной диагностике лимфом.Амплификация или перестройка гена CCND1, расположенного на хромосоме 11q13, и как следствие, гиперэкспрессия белка циклин D1 приводят к укорочению фазы G1, уменьшению размера клеток и потере контроля клеточного цикла [10,11].Кроме того, избыточная экспрессия циклина D1 нарушает экспрессию и других генов, участвующих в пролиферации и делении клеток (c-myc, c-jun и Cyclin A).Elaine S. Jaffe в журнале «Blood» еще в 2008 г. [12] представила наглядную схему эволюции понимания и идентификации МКЛ (рис.2). ",
"section_name": "ИСТОРИЯ ВОПРОСА",
"section_num": null
},
{
"section_content": "МКЛ является гетерогенным заболеванием с широким спектром клинических проявлений от редких индолентных случаев, не требующих немедленного начала терапии, до агрессивных, быстро пролиферирующих типов опухоли.Разное клиническое поведение имеет серьезное молекулярное обоснование, которое позволило в новой классификации ВОЗ разделить опухоль на два варианта.Классическая МКЛ (80-90 % случаев) происходит из наивных В-клеток прегерминального этапа дифференцировки, отличается отсутствием мутаций генов IGHV, обычно SOX11-позитивная, проявляется нодальным/экстранодальным вовлечением и агрессивным течением (рис.3). Напротив, более редкий индолентный ненодальный тип МКЛ (10-20 %) характеризуется нали- Рис. 2. Схема эволюции понимания и идентификации МКЛ (цит.по [12]).МКЛ в Кильской классификации и модифицированной классификации Раппапорта рассматривалась в группах центроцитарной лимфомы и лимфоцитарной лимфомы промежуточной степени дифференцировки.В это время еще отсутствовали точные критерии идентификации морфологически сходных форм лимфоидных опухолей.Определение характерного иммунофенотипа МКЛ (CD5+, CD23-, CD10-) помогло в дифференциальной диагностике мелкоклеточных опухолей (ФЛ, ХЛЛ, ЛМЗ).Выявление в абсолютном большинстве случаев t(11;14)(q13;q32) позволило в рутинной практике использовать в диагностике МКЛ иммуногистохимическое определение белка циклин D1.Кроме того, вторичные генетические события, такие как делеция/мутация p53 и p16, были идентифицированы при ряде агрессивных подвариантов МКЛ, которые ранее гистологически обозначались как бластоидный подтип.Все вышеперечисленное позволило четко обозначить границы нозологически очерченного варианта лимфоидной злокачественной опухоли, обозначенного как мантийноклеточная лимфома ВДЛ -высокая степень дифференцировки, лимфоцитарная; ДГЛ -диффузная гистиоцитарная лимфома; ЛМЗ -лимфома маргинальной зоны; МКЛ -мантийноклеточная лимфома; НДЛ -низкая степень дифференцировки, лимфоцитарная; ПДЛ -промежуточная степень дифференцировки, лимфоцитарная; ФЛ -фолликулярная лимфома; ХЛЛ -хронический лимфолейкоз.[12]).The Kiel classifi cation and the modifi ed Rappaport classifi cation regarded MCL within centrocytic and lymphocytic lymphoma groups with intermediate grade of diff erentiation.At that time there were no precise criteria for identifying morphologically similar forms of lymphoid tumors.Determination of specifi c MCL immunophenotype (CD5+, CD23-, CD10-) helped in the diff erential diagnosis of small cell tumors (FL, CLL, MZL).Identifi cation of t(11;14)(q13;q32) in the vast majority of cases allowed to use immunohistochemical determination of Cyclin D1 protein in the routine practice for MCL diagnosis.Besides, secondary genetic events, such as p53 and p16 deletion/mutation, were identifi ed in several aggressive MCL subvariants which had been previously histologically designated as blastoid subtype.All said above allowed to mark the boundaries of nosologically distinct variant of lymphoid malignant tumor designated as mantle cell lymphoma ВДЛ -well-differentiated lymphocytic lymphoma; ДГЛ -diffuse histiocytic lymphoma; ЛМЗ -marginal zone lymphoma; МКЛ -mantle cell lymphoma; НДЛ -poorly differentiated lymphocytic lymphoma; ПДЛ -lymphocytic lymphoma of intermediate differentiation; ФЛ -follicular lymphoma; ХЛЛ -chronic lymphocytic leukemia.Этот комплекс способствует фосфорилированию главного гена-супрессора опухолевого роста -гена ретинобластомы (RB1).Инактивация RB1, опосредованная комплексом Cyclin D1-CDK4 или делецией гена RB1 (наблюдается в 30 % МКЛ), приводит к высвобождению фактора транскрипции E2F, ключевого триггера перехода клеток из фазы G1 в S-фазу клеточного деления [14].Активность E2F может быть дополнительно повышена за счет амплификации гена MYC, что ассоциируется с бластоидным вариантом и крайне агрессивным течением заболевания [15,16].Описаны редкие случаи циклин D1-негативной МКЛ, при которой определяются перестройки в генах СCND2 и CCND3.Эта крайне редкая подгруппа циклин D1-/D2-/D3-негативной МКЛ отличается агрессивным течением с признаками дисрегуляции циклина E [17]. ",
"section_name": "ПАТОГЕНЕЗ И МОЛЕКУЛЯРНАЯ БИОЛОГИЯ",
"section_num": null
},
{
"section_content": "",
"section_name": "Fig. 2. Evolution in the understanding and identifi cation of MCL (quoted from",
"section_num": null
},
{
"section_content": "Следующим важным звеном в патогенезе опухоли является гиперэкспрессия транскрипционного фактора SOX11, который не встречается в нормальных В-лимфоцитах.SOX11-опосредованная активация PAX5 блокирует программу дифференцировки В-лимфоцитов путем подавления белка BLIMP1 и тем самым предотвращает попадание клеток МКЛ в герминативный центр [18,19].В опухолевых клетках белок SOX11 регулирует клеточную миграцию, инвазию и рост, участвует в ангиогенезе и служит маркером агрессивного течения заболевания [20,21].Кроме того, экспрессия SOX11 -решающий маркер при установлении диагноза в тех крайне редких случаях, когда, несмотря на отсутствие t(11;14)(q13;q32) с гиперэкспрессией циклина D1, опухоль по другим параметрам, включая профиль экспрессии генов, демонстрирует соответствие МКЛ [22]. В зависимости от функции вовлеченного гена молекулярные нарушения при МКЛ можно объединить в несколько подгрупп.Это нарушения, связанные с генами контроля клеточного цикла (CCND1, RB1, CDK2, CDK4, CDKN2A, CDKN1B, TP53, MYC), участия в сигнальном пути генотоксического стресса (TP53, ATM, CDKN2A, MDM2), регуляции апоптоза (BCL2, MDM2, TP53, CDKN2A), выживания и пролиферации клеток (TRAF2, BIRC3, CARD11) и, наконец, генами эпигенетической модификации (NSD2/WHSC1, MLL2, MLL3) [23].Наиболее частыми являются мутации генов ATM (40-50 %), CCND1 (14-35 %), TP53 (14-31 %), MLL3 (16 %), MLL2 (12-20 %), TRAF2 (7-10 %), RB1 (10 %), NOTCH1 (5-14 %).В одних случаях, например при вовлечении гена АТМ, увеличивается генетическая нестабильность опухоли, однако нет данных о неблагоприятном влиянии этой генетической поломки на прогноз МКЛ [24].Другие, например мутация ТР53, относятся к маркерам крайне агрессивного течения заболевания [25].Изучение и понимание механизмов развития опухоли позволяют идентифицировать ключевые гены, вовлеченные в патогенез заболевания, и использовать их в дальнейшем в качестве мишеней для таргетной терапии. ",
"section_name": "Рис. 3. Последовательные этапы патогенеза классической (нодальной) и индолентной (ненодальной) мантийноклеточной лимфомы (МКЛ) (цит. по [13])",
"section_num": null
},
{
"section_content": "МКЛ составляет около 2-10 % всех неходжкинских лимфом.Медиана возраста составляет 60 лет, муж-чины болеют значительно чаще, чем женщины (2:1).Заболевание обычно протекает с генерализованной лимфаденопатией, гепатоспленомегалией и поражением костного мозга.Нередко диагностируется значимый лейкоцитарный лимфоцитоз, что требует дифференциальной диагностики с другими мелкоклеточными лимфомами.При бластоидном варианте с высоким лейкоцитозом необходимо исключить острый лейкоз.Из экстранодальных поражений часто наблюдается вовлечение ЖКТ, кольца Вальдейера, орбиты.Локальные стадии заболевания крайне редки. Европейская группа по изучению МКЛ провела большой ретроспективный анализ (1998-2015 гг.) данных пациентов, у которых опухоль проявлялась изолированным или преимущественно изолированным экстранодальным вовлечением по типу MALT (MALT МКЛ).В работу были включены клинические данные 127 больных (61 % мужчин) с медианой возраста 65 лет.Зоны поражения распределялись следующим образом: кольцо Вальдейера (32 %), ЖКТ (25 %), орбита (13 %), слюнные железы (13 %), другие локализации (1 %).При медиане наблюдения 80 мес.5-летняя выживаемость без прогрессирования (ВБП) составила 45 %, общая выживаемость (ОВ) -71 %.В сравнении со 128 больными с классической МКЛ за тот же период времени показатели отдаленной выживаемости при MALT MКЛ оказались статистически значимо лучше: медиана ВБП 4,5 vs 2,8 года (p = 0,001), медиана ОВ 9,8 vs 6,9 года (p = 0,018) соответственно.Таким образом, кроме описанного в классификации ВОЗ индолентного подварианта следует иметь в виду наличие отдельной клинической формы MALT МКЛ, которая также характеризуется относительно благоприятным прогнозом и не требует интенсивных режимов терапии [26]. Для определения индивидуального прогноза ОВ на примере 455 случаев классической МКЛ был разработан международный прогностический индекс (MIPI).Он позволяет стратифицировать пациентов на три группы: низкий (44 % больных, медиана ОВ не достигнута), промежуточный (35 %, медиана ОВ 51 мес.) и высокий риск (21 %, медиана ОВ 29 мес.) [27]. В качестве независимых неблагоприятных факторов были выбраны возраст, соматический статус по ECOG, уровень лактатдегидрогеназы и число лейкоцитов в крови (табл.1).Каждый прогностический признак оценивается от 0 до 3 баллов (сумма не должна превышать 11 баллов): низкий (0-3 балла), промежуточный (4-5 баллов), высокий риск (6-11 баллов). Позднее проведено другое крупное исследование, в котором наряду с клиническими параметрами 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Общая выживаемость 1 2 3 4 5 6 7 8 9 10 11 12 13 ",
"section_name": "КЛИНИЧЕСКИЕ ПРОЯВЛЕНИЯ, ФАКТОРЫ ПРОГНОЗА",
"section_num": null
},
{
"section_content": "Результаты молекулярно-генетических исследований при МКЛ позволили установить наличие большого числа повторяющихся нарушений генов, участвующих в регуляции клеточного цикла, репарации ДНК и эпигенетической модификации [28].Показано негативное влияние мутации генов TP53, NOTCH1 и NOTCH2 на прогноз заболевания [29][30][31].Скандинавская группа по изучению лимфом провела серьезный анализ прогностической ценности повторяющихся генетических аберраций в образцах костного мозга 183 первичных молодых пациентов с МКЛ, которые получали интенсивные режимы терапии в рамках протоколов MCL2 и MCL3 [32].Показано, что наибольшее независимое неблагоприятное влияние на ОВ оказывает наличие мутации ТР53, которая определялась у 11 % больных.В этой подгруппе у 50 % пациентов диагностированы рецидивы в течение 1-го года, а медиана ОВ составила 1,8 года по сравнению с 12,7 года у больных МКЛ с TP53 без мутаций (p < 0,0001).Мутации TP53 четко ассоциировались с индексом Ki-67 > 30 %, бластоидной морфологией, высоким риском по MIPI и плохим ответом на терапию (рис.6). Таким образом, наличие мутации гена TP53 позволяет идентифицировать фенотипически отличную и высокоагрессивную форму MКЛ, которую не удается контролировать содержащими цитарабин режимами и высокодозной химиотерапией (ВДХТ) с трансплантацией аутологичных гемопоэтических стволовых клеток (аутоТГСК).Определение статуса ТР53 ко времени диагностики позволяет выделить эту ",
"section_name": "Б",
"section_num": null
},
{
"section_content": "Рис. 6. Общая выживаемость больных МКЛ в зависимости от мутационного статуса гена ТР53 (цит.по [32]) ",
"section_name": "Мантийноклеточная лимфома",
"section_num": null
},
{
"section_content": "Современные подходы к лечению первичных больных МКЛ продолжают изменяться по мере накопления данных о молекулярных механизмах развития болезни и появления новых лекарственных средств.Выбор программы терапии зависит от биологических особенностей опухоли, возраста и соматического статуса пациента, наличия и тяжести сопутствующих заболеваний.В большинстве случаев МКЛ отличается агрессивным течением и требует начала противоопухолевой терапии.Вместе с тем примерно в 10-20 % случаев опухоль можно охарактеризовать как индолентную.Американские коллеги [33] предложили использовать термин «тлеющая» МКЛ, которая имеет ряд клинико-морфологических и других характеристик (табл.2).Для этой категории больных, а также при бессимптомном лейкемическом небластоидном варианте допустима тактика «наблюдай и жди». ",
"section_name": "ЛЕЧЕНИЕ",
"section_num": null
},
{
"section_content": "Перед началом терапии специалисту необходимо ответить на два основных вопроса: является ли больной кандидатом для интенсивных режимов, включая ВДХТ с аутоТГСК, и с учетом конкретной ситуации (доступность трансплантационных стационаров, предпочтения пациента) видит ли он ограничения в реальной возможности выполнения аутоТГСК.Ответы на эти два вопроса позволяют принять правильное решение по выбору адекватной терапии (табл.3). В том случае, если у больного нет противопоказаний для получения интенсивных режимов, но существуют опасения невозможности своевременного проведения аутоТГСК, программой выбора может служить режим R-HyperCVAD/R-MA, который не тре-бует высокодозной консолидации.Согласно данным американских ученых, которые лечили 97 больных МКЛ по этой программе без аутоТГСК, при медиане наблюдения более 1 3 лет общая эффективность (ОЭ) терапии составила 97 %, а медиана ВБП у молодых пациентов была 78 мес.[34].В дальнейших исследованиях было показано, что добавление бортезомиба к этому режиму не улучшило результаты лечения по сравнению с оригинальной программой R-Hyper-CVAD/R-МА [35].Несмотря на эффективность, данный вид терапии характеризуется высокой гематологической токсичностью и значительным числом вторых опухолей (6,2 %).Так, согласно данным итальянских авторов (n = 60) и группы SWOG (n = 49), только у 40 и 60 % больных соответственно удалось завершить полную программу в связи с высокой ее токсичностью [36,37]. В Европе более распространены интенсивные режимы индукции, включающие цитарабин в высоких дозах с последующей консолидацией ВДХТ и аутоТГСК [38,39].В качестве индукционных режимов рассматриваются альтернирующие схемы R-CHOP/R-DHAP (European MCL network) или R-maxi-CHOP/R-HD-araC (Nordic group).Результаты этих двух режимов вполне сопоставимы: медиана ВБП составляет 8,5-9 лет.Все перечисленные выше протоколы, с одной стороны, демонстрируют преимущества в добавлении цитарабина в высоких дозах, с другой -ставят под сомнение целесообразность сохранения R-CHOP в программе.В небольшом исследовании показана эффективность альтернирующего режима BR/R-HD-araC у 23 Таким образом, в настоящее время стандартом лечения первичных молодых (< 65 лет) больных с МКЛ являются интенсивные режимы иммунохимиотерапии с включением цитарабина в высоких дозах, консолидация ВДХТ с аутоТГСК и дальнейшая поддерживающая терапия ритуксимабом.Какие изменения в этой стратегии ожидают нас в будущем?С одной стороны, возможна интенсификация лечения с включением новых препаратов (ингибиторы тирозинкиназы Брутона [BTK]) и аллоТКМ в группе крайне высокого риска с мутацией ТР53.С другой стороны, это попытка деэскалации с отказом от высокодозной консолидации у больных, достигших МОБ-отрицательной ремиссии (исследование E4151, № NCT03267433), или применение «chemo-free window» (нехимиотерапевтическое окно) режима (ибрутиниб + ритуксимаб) с коротким курсом консолидации HyperCVAD без дальнейшего высокодозного этапа (исследование Window-1, № NCT02427620).Ответы на эти и другие вопросы ожидают нас в ближайшие 2-3 года. ",
"section_name": "Первая линия лечения молодых больных МКЛ",
"section_num": null
},
{
"section_content": "Медиана возраста больных составляет 60-65 лет, а значит, лечение именно этой популяции представляет основную проблему при МКЛ.В качестве первой линии терапии рассматриваются содержащие антрациклин или бендамустин режимы [42].В основе большого рандомизированного исследования M. Rummel и соавт.было как раз сравнение режимов R-CHOP и BR у первичных больных с индолентными лимфомами и МКЛ.Последняя группа была представлена 94 пациентами [43].Бендамустин продемонстрировал высокую эффективность и благоприятный профиль токсичности у всей анализируемой группы.При МКЛ медиана ВБП составила 35 и 22 мес.соответственно (p = 0,0044), различий в ОВ не получено.Эти данные были подтверждены в протоколе BRIGHT [44] Таким образом, в лечении пожилых отчетливо прослеживаются две сопоставимые по эффективности программы (BR и R-CHOP + Rmaint), которые, однако, позволяют получить длительные ремиссии только у половины больных.Безусловно, исследователями предпринимаются попытки улучшить эти результаты путем добавления новых препаратов.Первой попыткой были замена винкристина на бортезомиб и проведение рандомизированного сравнения режимов R-CHOP и VR-CAP у больных МКЛ, у которых не планируется ВДХТ [46].В протокол включено 487 первичных больных МКЛ.При медиане наблюдения 40 мес.медиана ВБП была статистически значимо выше в группе с бортезомибом (30 и 16 мес.соответственно; p = 0,0044).Однако это лечение оказалось более токсичным за счет большого числа серьезных тромбоцитопений (57 %).Интересен тот факт, что при более длительном сроке наблюдения (медиана 82 мес.) различия в ОВ после применения VR-CAP стали особенно очевидными (медиана ОВ 90 и 55 мес.соответственно; p = 0,001) [47]. Австралийские коллеги провели важный анализ результатов лечения 70 больных МКЛ (медиана возраста 69 лет) по содержащим антрациклин режимам с или без добавления цитарабина [48].Были проанализированы следующие режимы: R-CHOP-like (n = 39), R-CHOP/R-DHAC (n = 10), R-HyperCVAD/R-MA (n = 7), R-CHOP/Cytarabine (Nordic Protocol) (n = 10) и другие (n = 4).ВДХТ с аутоТГСК выполнена 16 больным.При медиане наблюдения 37 мес.содержащие цитарабин режимы в сравнении с R-CHOP показали лучшие результаты ОЭ (70 и 33 % соответственно; p < 0,001) и отдаленной выживаемости (p = 0,05).Однако они отличались более высокой токсичностью и были выполнимы у относительно молодых больных МКЛ.В такой ситуации итальянские коллеги [49,50] предложили добавлять цитарабин к менее токсичной схеме BR (сначала Ara-C по 800 мг/м 2 в 1-3-й день, затем доза из-за гематологической токсичности была снижена после первого анализа до 500 мг/м 2 в 1-3-й день).Режим R-BAC был протестирован у 57 больных (медиана возраста 71 год) и продемонстрировал удовлетворительные результаты: ОЭ 96 % (МОБ-отрицательные ремиссии 55 %), 2-летняя ВБП 83 %, 2-летняя ОВ 91 %.Следует отметить, что у 49 % пациентов отмечалась нейтропения II-IV степени и у 52 %тромбоцитопения; выполнить все 6 циклов удалось только у 63 % больных.Тем не менее режим R-BAC представляется перспективной опцией лечения МКЛ.Основные режимы первой линии лечения пожилых больных представлены в табл.4. В лечении пожилых больных МКЛ продолжается поиск баланса между эффективностью и токсичностью.В этом контексте чрезвычайно интересным представляется применение режимов «chemo-free».Наиболее изученной является схема R2, которая включает индукционный этап и поддерживающее лечение максимально до 3 лет: леналидомид 20 мг в 1-21-й день каждые 28 дней (всего 12 циклов), затем леналидомид по 15 мг в режиме поддержки + ритуксимаб еженедельно (4 введения), далее каждые 2 мес.[51].В протокол включено 38 пожилых больных МКЛ, причем 1 / 3 из них составляла группу высокого риска по MIPI.При медиане наблюдения 64 мес.5-летняя ВБП составила 64 %, 5-летняя ОВ -77 %. Продолжается большое число исследований с включением новых препаратов (ибрутиниб, акалабрутиниб) в комбинации с ритуксимабом или обинутузумабом, которые изучаются в первой линии терапии у пожилых больных МКЛ.Интересными представляются следующие протоколы лечения, результаты которых ожидаются в скором времени: Для контроля долгосрочной эффективности лечения больных МКЛ важна оценка МОБ как основного Г.С.Тумян КЛИНИЧЕСКАЯ ОНКОГЕМАТОЛОГИЯ маркера качества противоопухолевого ответа и риска развития рецидива [52].Вместе с тем в отличие от хронического лимфолейкоза МОБ при МКЛ изучена недостаточно, поскольку не у всех больных имеется поражение костного мозга ко времени диагностики или достаточно высокий опухолевый лимфоцитоз в крови, который можно оценить проточной цитофлюориметрией или аллель-специфической ПЦР.В этой связи интересным представляется использование новых методов обнаружения IgH-клона или количественный ПЦР-анализ t(11;14)(q13;q32) периферической крови больных МКЛ [53].Применение ритуксимаба, ингибиторов BTK или леналидомида в качестве поддерживающей терапии может служить инструментом для достижения МОБ-отрицательной ремиссии. ",
"section_name": "Первая линия лечения пожилых больных МКЛ",
"section_num": null
},
{
"section_content": "Несмотря на успехи в лечении больных МКЛ, заболевание считается неизлечимым.Американские ученые из Memorial Sloan Kettering Cancer Center (MSKCC) провели большой ретроспективный анализ своей базы данных за 15 лет (2000-2014 гг.).В исследование включено 404 больных МКЛ, которые получали лечение и наблюдались в этом центре на протяжении указанного периода времени [54].Этот анализ предоставляет уникальную возможность проследить за течением заболевания, оценить эффективность множественных линий терапии.Согласно их данным, каждая последующая ремиссия при МКЛ значительно короче предыдущей, а срок жизни больных неизбежно уменьшается.Так, медиана ОВ после первой линии составила 116,3 мес., а далее -41, 25, 14 и, наконец, 8,6 мес.соответственно линиям терапии; медиана ВБП -47, 14, 6, 5 и 3,2 мес.соответственно (рис.7).Тем не менее необходимо отметить, что медиана ОВ больных, у которых заболевание диагностировано после 2000 г., превышает 11 лет, в то время как до 1990 г. этот показатель не достигал 3 лет [55].Это связано с интенсификацией лечения и внедрением новых эффективных лекарственных средств.Особого внимания требуют больные МКЛ с ранним рецидивом или прогрессированием опухоли: медиана ВБП и ОВ после первого раннего рецидива составляет 9,6 и 29,9 мес.соответственно.Наиболее эффективны режимы первой и второй линий, все последующие линии терапии у больных МКЛ не различаются по длительности ремиссии и составляют в среднем менее 6 мес. Полученные результаты вновь указывают на то, что на ранних этапах течения болезни необходимо внедрять новые препараты в схемы терапии и комбинировать лекарственные средства с различным механизмом действия.Представляем перечень перспективных новых препаратов, которые уже успешно применяются или проходят испытания при рецидивах МКЛ.Венетоклакс -селективный ингибитор антиапоптотического белка Bcl-2 для приема внутрь.Гиперэкспрессия Bcl-2 обычно наблюдается при различных В-клеточных опухолях, в т. ч. и при МКЛ, и способствует выживанию клеток, блокируя в них апоптоз.В I фазу клинического исследования включено 28 больных с рецидивами МКЛ (медиана возраста 72 года, в среднем три линии предшествующей терапии).Препарат оказался эффективным в 75 % наблюдений с частотой ПР у 21 % больных и с медианой ВБП 14 мес.[64].Обнадеживающие результаты получены при использовании комбинации венетоклакса с ибрутинибом в рамках протокола AIM [65].В анализ включены данные 23 больных (75 % пациентов имели высокий риск по MIPI, у 50 % определялась мутация TP53).Эта комбинация оказалась эффективной в 71 % случаев (ПЭТ-отрицательные ремиссии у 62 % больных).Медиана ВБП не достигнута, 12-месячная ВБП составила 75 %.Особо следует отметить, что у половины больных с мутацией ТР53 (n = 12) достигнута ПР.Основным побочным эффектом III-IV степени была диарея (71 %) и нейтропения (33 %).Венетоклакс имеет большой потенциал в лечении больных МКЛ, особенно в случае прогрессирования после применения ингибиторов BTK. ",
"section_name": "РЕЦИДИВЫ",
"section_num": null
},
{
"section_content": "Ингибиторы mTOR-киназы и других сигнальных путей.Наиболее изученным при рецидивах МКЛ из группы ингибиторов mTOR представляется темсиролимус, который применялся в дозе 175 мг еженедельно в течение 3 нед., далее по 75 мг еженедельно до прогрессирования или непереносимой токсичности.Препарат вводился внутривенно, что затрудняло его длительное применение, при этом частота общего ответа составила 22 %, а медиана ВБП не превышала 4,8 мес.[66]. Ингибиторы PI3K являются перспективным классом препаратов в лечении больных с рецидивами МКЛ, особенно после терапии ибрутинибом.Первый в этом классе ингибитор PI3K-δ иделалисиб показал активность при различных В-клеточных опухолях, в т. ч. и при МКЛ [67].Парсациклиб (ингибитор PI3Kδ второго поколения), энтосплентиниб (ингибитор SYK-киназы) и энзастаурин (протеинкиназа С, PKC) сейчас проходят клиническое исследование при рецидивах МКЛ. ",
"section_name": "НОВЫЕ ПЕРСПЕКТИВНЫЕ ПРЕПАРАТЫ",
"section_num": null
},
{
"section_content": "Иммунотерапия.Ингибиторы контрольных иммунных точек (ипилимумаб, ниволумаб, пембролизу маб) и биспецифические моноклональные антитела (блинатумомаб) представляются определенным прорывом в лечении солидных опухолей и различных гематологических злокачественных опухолей (лимфома Ходжкина, лимфобластная лимфома).Однако при МКЛ отмечается очень низкая экспрессия PD-L1, PD-L2 на опухолевых клетках и не определяются РD1-экспрессирующие Т-лимфоциты в окружающей ткани при биопсии.Этим можно объяснить неэффективность перечисленных выше препаратов при МКЛ. Одним из примеров адоптивной иммунотерапии являются генетически модифицированные Т-лимфоциты, экспрессирующие химерные антигенные рецепторы (CAR T-клетки), которые широко применяются при агрессивных лимфомах.В исследовании I фазы ZUMA-2 изучается эффективность аутологичных анти-CD19 CAR T-лимфоцитов (KTE-C19) у больных с рецидивами МКЛ [33].Другим видом CAR T-клеточной терапии (JCAR-017) является СD19-направленный 4-1BB CAR T-клеточный продукт, применяемый при рецидивах МКЛ.Эти два протокола проходят первый этап изучения, но могут стать потенциально важным направлением в лечении рецидивов МКЛ после применения ингибиторов BTK. АллоТКМ рекомендуется больным из группы высокого риска с мутациями ТР53 при рецидивах МКЛ.Эта стратегия позволяет получить длительный контроль над болезнью примерно у 30 % больных [33]. ",
"section_name": "Мантийноклеточная лимфома",
"section_num": null
},
{
"section_content": "Последние десятилетия расширили наши знания о биологии и клональной эволюции МКЛ.Алгоритмы лечения, основанные на интенсивной химиоте-рапии, с включением цитарабина в высоких дозах, аутоТГСК с дальнейшей поддерживающей терапией ритуксимабом позволили длительно контролировать заболевание у значительного числа больных.С другой стороны, появление инновационных лекарственных средств (ингибиторы BTK, леналидомид, венетоклакс) с уникальным механизмом действия расширило возможности лечения рецидивов заболевания.Дальнейшее изучение различных молекулярных нарушений позволит в будущем стратифицировать больных МКЛ на группы риска и проводить адаптированную терапию с учетом МОБ-статуса (рис.9). Применение новых препаратов вселяет надежду на возможность ухода от традиционной химиотерапии у определенной части больных.Основной целью лечения МКЛ станет рациональная комбинация препаратов с эффективным уничтожением остаточного клона, что в итоге может привести к долгосрочному контролю заболевания. ",
"section_name": "ЗАКЛЮЧЕНИЕ",
"section_num": null
},
{
"section_content": "Автор заявляет об отсутствии конфликтов интересов.Г.С.Тумян, член редакционной коллегии журнала «Клиническая онкогематология.Фундаментальные исследования и клиническая практика», не участвовала в рецензировании рукописи. ",
"section_name": "КОНФЛИКТЫ ИНТЕРЕСОВ",
"section_num": null
},
{
"section_content": "Исследование не имело спонсорской поддержки.Рис. 9. Настоящее и будущее лечения МКЛ (цит.по [13]) BTK -тирозинкиназа Брутона; МКЛ -мантийноклеточная лимфома; МОБ -минимальная остаточная болезнь. ",
"section_name": "ИСТОЧНИКИ ФИНАНСИРОВАНИЯ",
"section_num": null
},
{
"section_content": "",
"section_name": "ЛИТЕРАТУРА/REFERENCES",
"section_num": null
}
] | [] |
10.3390/onco4030013 | A Systems Biology Analysis of Chronic Lymphocytic Leukemia | "<jats:p>Whole-genome sequencing has revealed that TP53, NOTCH1, ATM, SF3B1, BIRC3, ABL, NXF1, BCR, (...TRUNCATED) | [{"section_content":"Chronic lymphocytic leukemia (CLL) is a type of cancer that affects white blood(...TRUNCATED) | [{"section_content":"Funding: J.A.T. acknowledges the funding support received from NSERC (Canada) f(...TRUNCATED) |
10.18632/oncotarget.27080 | "Methylation alteration of <i>SHANK1</i> as a predictive, diagnostic and prognostic biomarker for ch(...TRUNCATED) | "Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the clona(...TRUNCATED) | [{"section_content":"Chronic lymphocytic leukemia (CLL), one of the most common mature B cell neopla(...TRUNCATED) | [{"section_content":"www.oncotarget.comThe Melbourne Collaborative Cohort Study (MCCS) recruitment w(...TRUNCATED) |
10.1371/journal.pone.0013262 | "Tumor Necrosis Factor-α Regulates Distinct Molecular Pathways and Gene Networks in Cultured Skelet(...TRUNCATED) | "Skeletal muscle wasting is a debilitating consequence of large number of disease states and conditi(...TRUNCATED) | [{"section_content":"Skeletal muscle atrophy or wasting is a common phenomenon in a large number of (...TRUNCATED) | [{"section_content":"This work was supported by National Institutes of Health grant RO1 AG029623 to (...TRUNCATED) |
10.3390/cardiogenetics13030010 | GMDS Intragenic Deletions Associate with Congenital Heart Disease including Ebstein Anomaly | "<jats:p>Ebstein anomaly is a rare heterogeneous congenital heart defect (CHD) with a largely unknow(...TRUNCATED) | [{"section_content":"Ebstein anomaly is a rare congenital heart defect in which the tricuspid valve (...TRUNCATED) | [{"section_content":"The data presented in this study are available on request from the correspondin(...TRUNCATED) |
10.7554/elife.98747.3 | "The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor pro(...TRUNCATED) | "<jats:p>The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis (...TRUNCATED) | [{"section_content":"The skin is a vital organ that acts as a protective barrier against the externa(...TRUNCATED) | [{"section_content":"We are grateful to C Cottonham, S Hankeova, and G Hernandez for their helpful d(...TRUNCATED) |
10.3390/jcdd2040248 | Embryonic Development of the Bicuspid Aortic Valve | "<jats:p>Bicuspid aortic valve (BAV) is the most common congenital valvular heart defect with an ove(...TRUNCATED) | [{"section_content":"Congenital heart disease (CHD) is the most frequently occurring birth defect am(...TRUNCATED) | [{"section_content":"This work was supported by a National Institutes of Health grants 1R01HL114823 (...TRUNCATED) |
10.3390/cells9061484 | Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL | "<jats:p>NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia ((...TRUNCATED) | [{"section_content":"Chronic lymphocytic leukemia (CLL) is considered an antigen-driven B-cell neopl(...TRUNCATED) | [{"section_content":". ID Age Gender Rai/Binet Stage IGHV Status Cytogenetic Alterations NOTCH1 Muta(...TRUNCATED) |
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in Data Studio
SciLake Fulltext Corpus
The SciLake Fulltext Corpus is a collection of scientific papers parsed and segmented by section, primarily designed for research in the development and evaluation of NLP models. This dataset contains 1,000 full-text papers from various scientific domains, including Neuroscience, Cancer, Transport, and Energy, along with an additional 5,000 random papers from general scientific domains. All papers have been curated with licenses that allow for legal usage, specifically CC-BY and Public Domain.
The dataset provides detailed metadata and full-text sections, offering a robust resource for domain-specific and general scientific research, dataset annotation, model training, and evaluation.
Corpus Overview
- 1,000 Full-Text Papers Segmented by Section:
- Domain-specific sections: Neuroscience 🧠, Cancer 🦀, Transport 🛻, Energy 🪫.
- Each paper is segmented into sections such as Introduction, Methods, Results, etc.
- 5,000 Random Papers from General Scientific Domains:
- Mix of stratified sampled by MAG level 0 to ensure diversity across multiple domains and disciplines, and random sample.
Example of Dataset Structure:
{
'doi': DOI,
'title': TITLE,
'description': ABSTRACT,
'fulltext_sections': [
{
'section_name': SECTION_NAME_1,
'section_num': SECTION_NUM_1,
'section_content': SECTION_CONTENT_1,
},
...
],
'fulltext_additional': [
{
'section_name': SECTION_NAME_1,
'section_num': SECTION_NUM_1,
'section_content': SECTION_CONTENT_1,
},
...
]
How to use
from datasets import load_dataset
dataset_ds = load_dataset("SIRIS-Lab/scilake-fulltext-corpus")
Licensing Information
The SciLake Fulltext Corpus is released under the following licenses:
CC-BY (Creative Commons Attribution), licenses have been obtained from the publisher’s landing page, PDFs, metadata in OpenAire, and Unpaywall, filtering fro those with license CC-BY or Public Domain.
Dataset Acquisition
The papers included in this dataset were sourced through the OpenAIRE index, with random selection to ensure diverse content. The license information was verified by cross-referencing the publisher’s landing pages, metadata from OpenAire, and the Unpaywall database. Papers were retained if they had a CC-BY license or were in the Public Domain.
Funding
This work was partially funded by a projects under EU’s HORIZON Research and Innovation Programme:
- SciLake (grant agreement No 101058573).
Contact
For more information, or if you have questions, please contact us at sirislab[at]sirisacademic.com.
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