bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Characteristics and Outcome of Patients (pts) with T315I Mutation after Imatinib Failure.
Authors: Jabbour Elias , Kantarjian Hagop , Jones Dan , Giles Francis , Borthakur Gautam , O’Brien Susan , Cortes Jorge 
Published: October 2019

Point mutations of the Bcr-Abl kinase domain are the most frequently identified mechanism of resistance in patients (pts) with CML who failed imatinib. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant to imatinib as well as to the novel tyrosine kinase inhibitors (NTKIs) (eg, dasatinib, nilotinib) both in vitro and in vivo. It has thus been suggested that these pts have a very poor prognosis. To define the clinical characteristics and outcome of these pts, we reviewed all pts with this mutations identified at our institution after failure to imatinib. T315I was detected in 15 of 112 patients (13%) harboring kinase domain mutations. Median age was 49 years (range, 34-66 years). At the time imatinib was started, 12 pts were in chronic (CP) and 3 in accelerated (AP). Ten pts had received prior interferon therapy. The best response to imatinib was major molecular response in 1, major cytogenetic response in 5 (complete in 2), and complete hematologic response in 8. One patient was intolerant to imatinib. The median duration of response was 37 months (range, 10–60 months). T315I was identified after a median of 48 months (range, 10–83 months). At the time the mutation was identified, 9 patients had transformed (7 to AP, 2 to BP). Clonal evolution was observed in only 1 pt. Fourteen patients received subsequent NTKIs; 3 of them received both nilotinib and dasatinib. Among them, 1 patient achieved a partial hematologic response with nilotinib that lasted for 3 months and 1 other had T315I identified while in complete cytogenetic response induced by nilotinib that has been sustained for 16+ months. After a median follow-up of 27 months (range, 3–42 months), 11 pts (73%) are alive: 8 are alive with active disease, and 3 patients are alive with ongoing response: 1 in complete molecular remission following allogeneic stem cell transplantation, 1 in partial cytogenetic response following treatment with aurora kinase inhibtor MK0457, and one in sustained complete cytogenetic response with ongoing treatment with nilotinib. Four patients have died of disease progression. Except for previous treatment with interferon (more frequent in patients harboring the T315I mutation; p=0.024) and the lack of response to the NTKI (p=0.001), there was no difference in patients characteristics and previous response to imatinib compared to patients with other mutations.
Similarly, there was no difference in overall survival among patients with T315I mutations or other mutations (p=0.71). In conclusion T315I is a highly resistant mutation to conventional tyrosine kinase inhibitors; however occasional responses can be observed and overall survival may not be as poor as previously reported.
In Vitro and In Vivo Evidence That TSC-22 Is a Putative Tumor Suppressor Gene in Primary Murine and Human Leukemia.
Authors: Yu Jianhua , Yu Li , Hackanson Bjoern , Wei Min , Boyd Zachary , Yokohama Akihiko , Liu Chunhui , Trotta Rossana , Mao Hsiaoyin C. , Becknell Brian , Jaung Michael S. , Liu Shujun , Byrd John C. , Marcucci Guido , Plass Christoph , Caligiuri Michael A. 
Published: October 2019

Abstract
Transforming growth factor-β-stimulated clone-22 (TSC-22) is a gene that has been shown to be silenced in brain and prostate cancer, but its function and the mechanism responsible for this silencing are unknown. We used our model of spontaneous T-natural killer (NK) acute lymphoblastic leukemia (ALL) and discovered that the TSC-22 promoter was methylated resulting in absent expression in seven of eight cases of primary NK-T ALL, but not in cells from normal mice or mice with polyclonal expansion of T and NK cells. We found that TSC-22 was undetectable or minimally expressed in mouse lymphoma cell lines YAC-1 and EL-4 and human leukemia cell lines Jurkat and RPMI 8866, but treatment with the demethylation agent 5-aza-2′-deoxycytidine restored or increased TSC-22 expression. We mapped the TSC-22 promoter and discovered a CPG island in the proximal region and determined that its methylation was responsible for the decreased gene expression. Over-expression of TSC-22 slowed in vitro cell growth and resulted in a dramatic decrease of tumor size in vivo. Finally, TSC-22 expression was found to be absent or substantially reduced in human chronic lymphocytic leukemia and acute myeloid leukemia compared to normal human tissue. Collectively, our data indicate that TSC-22 is silenced via DNA methylation within its proximal promoter, and this silencing appears to contribute to its function as a putative tumor suppressor gene in leukemia. Silencing of TSC-22 can be reversed by 5-aza-2′-deoxycytidine, recently approved by the FDA for the treatment of myelodysplastic syndrome.
Distinct Expression Patterns of Human microRNAs in Myeloid Differentiation and Acute Myeloid Leukemia.
Authors: Isken Fabienne , Steffen Björn , Markus Birgit , Hömme Claudia , Kosel David , Illmer Thomas , Merk Sylvia , Dugas Martin , Berdel Wolfgang E. , Serve Hubert , Müller-Tidow Carsten 
Published: October 2019

Abstract
MicroRNAs (miRNAs) play an important role in differentiation, regulation of cell growth, cell death and potentially cancer pathogenesis. In the current study, we profiled expression of 154 human miRNAs by using a stem-loop reverse transcription and real-time PCR approach in 50 patients with AML and 12 control samples (normal bone marrow (NBM) samples and CD34+ cells). All of these samples were simultaneously analysed by whole genome mRNA microarrays. Out of all miRNAs tested, more than 30 were analyzed in a second, independent group of 48 AML samples and 4 controls. Five miRNAs showed differentiation associated expression changes which were confirmed by in-vitro differentiation of HL-60 cells with all-trans retinoic acid (ATRA) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Overall, we found six miRNAs, including the miR-221 and 222 cluster, that showed substantially different expression between AML and CD34+ cells/ NBM. In class prediction analyses using support vector machines, 92% of the AML samples and 100% of the control samples were correctly predicted. We also looked for differentially regulated miRNAs in FAB subtypes and identified several miRNAs with significantly different expression. For example, high expression levels of miR-26a, 23a and 27b occurred in FAB M5. mRNA levels were analyzed with regard to differences in miRNA expression. Significant negative correlations with specific mRNAs were observed for several miRNAs, for example miR-23b. When mRNA expression patterns were analyzed for dichotomized miRNA levels, close associations between specific miRNAs and gene expression clusters were observed. For example, miR-10a levels were closely associated with the expression of hox genes. Taken together, the distinct expression patterns of miRNAs observed in AML strongly suggest involvement of the described miRNAs in both hematopoietic differentiation and pathogenesis of AML.
G125A Single Nucleotide Polymorphism (SNP) in 5′-UTR of the Tumor Suppressor Gene Bax Affects Its Transcriptional Regulation.
Authors: Saxena Anurag , Bonham Keith , Neuls Evan , Moshynska Oksana 
Published: October 2019

Abstract
Lower expression of Bax protein in various human malignancies is associated with poor response to treatment and shorter disease-free survival. We (Cancer Lett2002; 187:199–205) and others (J Clin Oncol; 23:1514–21) have shown the association of a single nucleotide polymorphism (SNP) in the BAX promoter (G125A) with reduced protein expression and treatment resistance in chronic lymphocytic leukemia (CLL). Using luciferase reporter gene assay we demonstrated that this SNP significantly reduced BAX promoter activity (Oncogene2005; 24:2042–9). Our aim was to determine the effect of this polymorphism on the binding of transcription factors. For electrophoretic mobility shift (EMSA), HeLa and K562 nuclear extracts, and for chromatin immunoprecipitation (ChIP), K562 cells were used to study their ability to bind to a radiolabeled DNA probe corresponding to the BAX promoter region with G nucleotide at the position 125 or bearing G125A SNP. Super-shift assay was performed to determine the transcription factor involved in binding. Competition assays were performed to determine differences in the binding ability of the two probes. A panel of antibodies was tested by super-shift and ChIP assays, non-specific antibodies served as negative controls. Two major band shifts were detected by EMSA. The mobility of the detected complexes was different from those observed with GC1 probe, specific for Sp1/Sp3, suggesting the involvement of transcription factors other than Sp1/ Sp3. This was confirmed in super-shift assay and ChIP assay by incubating DNA probes with Sp1 or/ and Sp3 antibodies. We also found in the competition assays that the cold probes competed differently for binding. The findings provide evidence of the ability of G125A SNP to influence transcription factor binding in vitro (as shown in EMSA experiments) and in vivo (in ChIP experiments).
Leukotrienes Stimulate the Release of Cytokines and Proliferation of Hodgkin Reed-Sternberg Cells.
Authors: Sjoberg Jan , Schain Frida , Tryselius Ylva , Backman Linda , Malec Maria , Porwit-MacDonald Anna , Bjorkholm Magnus , Claesson Hans-Erik 
Published: October 2019

Abstract
Background: Classical Hodgkin Lymphoma (cHL) is characterized by a minority of malignant cells, the so-called Hodgkin- and Reed Sternberg (H-RS) cells, surrounded by inflammatory cells such as eosinophils, macrophages and mast cells. In contrast to other tumors, the malignant H-RS cells constitute only a few percent of the total cells in the affected tissue. Therefore, it is generally believed that various compounds released by H-RS cells and the interaction between H-RS cells and by- stander cells are of great importance in the pathophysiology of cHL disease.
Aim: To characterize the expression and function of cysteinyl leukotriene receptors (CysLTR) in cHL.
Methods and results: We have identified functional CysLT1R in a HL cell line as shown by increased intracellular calcium release upon leukotriene (LT) D4 stimulation (100–500 nM). This response was completely blocked after addition of zafirlukast, a specific CysLT1R antagonist. Immunohistochemical studies of paraffin embedded cHL tissue showed H-RS cells positive for CysLT1R in 12 of 16 cHL tumors. Microarray analysis of laser captured H-RS cells from 3 tumors not only confirmed the expression of CysLT1R transcripts, but also showed expression of the CysLT2R gene (P. Murray, personal communication). The possible role of the CysLT2R in H-RS cells will be discussed. The HL cell line was cultured in the presence of LTD4 (100 nM) to investigate the effects of CysLT signaling in H-RS cells. Real-time RT-PCR analysis showed up-regulation of TNF-α, interleukin (IL)-6, IL-8 and IL-13 mRNA after stimulation with LTD4. Furthermore, the effects of LTD4 on cytokine protein secretion by the HL cells were studied by flow cytometry. The results showed a markedly increased secretion of TNF-α, IL-6 and IL-8 upon LTD4 stimulation. In addition, LTD4 stimulated cell proliferation in a dose-dependent manner.
Conclusion: Since H-RS cells are surrounded by CysLT producing cells (eosinophils, macrophages and mast cells), these results indicate that CysLT signaling could be of importance in the pathogenesis of cHL by contributing to proliferation of the tumor cell population and the disturbed cytokine features of this tumor. This study was supported by the Swedish Cancer Society.
Increased Tumor Infiltrating FOXP3+ Regulatory T-Cells Are Associated with Improved Survival in Classical Hodgkin Lymphoma.
Authors: Kelley Todd W. , Pohlman Brad , Elson Paul , Hsi Eric D. 
Published: October 2019

Abstract
Background: Regulatory T-cells (Tregs), a CD4+, CD25+, FOXP3+ subset, appear to modulate the tumor microenvironment in lymphoma. Using FOXP3 expression as a marker of Tregs, single series have suggested that higher numbers of tumor infiltrating FOXP3+ cells are associated with improved survival in both follicular lymphoma and classical Hodgkin lymphoma (cHL). However, neither of these findings has been confirmed by separate studies and, in fact, contradictory data exists. We sought to evaluate potential correlations between the number of FOXP3+ cells in the tumor microenvironment and patient outcome.
Methods: 98 previously untreated cHL patients, biopsied and treated with curative intent at the Cleveland Clinic, were studied. FOXP3 was assessed by immunohistochemistry (Abcam) and quantitated as the number of positive cells per high power field (hpf), averaged over 5 fields. Histology was evaluated and medical records were reviewed for clinical features (including gender, age, stage, B symptoms, bulk, number of sites and IPS), lymphoma progression and death.
Results: The mean number of FOXP3+ cells (±standard deviation) was 41.7 ± 33.9 cells/hpf, and the median number was 36.4 cells/hpf (range 0–152.0 cells/hpf). Higher numbers of FOXP3+ T-cells were associated with age<45 (P=.02), stage I–II (P=.01), and IPS≤2 (P=.06) [Wilcoxon rank sum test]. 28 of the 98 patients (29%) have progressed and/or died and 20 (20%) have died. The estimated 5-year failure free survival (FFS) and overall survival (OS) are 76%±4% and 86%±4%, respectively. 70 patients remain alive with no evidence of disease at a median follow-up of 8.6 years (range 0.9–19.9 years). Recursive partitioning demonstrated an optimal cutoff of 25 FOXP3+ cells/hpf for analysis of outcome. Overall, 43 patients (44%) had a mean of <25.0 FOXP3+ cells/hpf and 55 (56%) had 25.0 or more. In univariate analysis, higher numbers of FOXP3+ T-cells in the tumor microenvironment were associated with better FFS; estimated 5-year FFS was 91% ± 4% for patients with >25.0 FOXP3+ cells/hpf compared to 81% ± 6% for patients with <25.0 (P=.05, generalized Wilcoxon test). There was also a trend towards improved OS (P=.10). In multivariate analysis, the number of FOXP3+ T-cells remained an independent predictor, even after adjusting for age, stage, and IPS ( P<.05). Kaplan-Meier curves for FFS and OS stratified by FOXP3+ “status” are shown in Figures 1 and 2.
Conclusion: FOXP3+ T cells are a favorable prognostic marker in cHL and reflect the importance of the immune response thus providing rationale for the use of immunomodulatory therapies in these patients.
Failure Free Survival Failure Free Survival
Overall Survival Overall Survival
TARC and MDC Are the Only Chemokines with Highly Increased Levels in Serum of Hodgkin Lymphoma Patients.
Authors: Niens Marijke , Visser Lydia , Jarrett Ruth F. , te Meerman Gerard J. , Poppema Sibrand , van den Berg Anke 
Published: October 2019

Abstract
Chemokines (cytokines with chemoattractant properties) can recruit different subsets of cells and therefore play an important role in the formation and maintenance of the non-neoplastic reactive infiltrate present in Hodgkin lymphoma (HL). The infiltrate consisting of lymphocytes, plasma cells, histiocytes and eosinophilic granulocytes is the most abundant part of the tumor mass in HL and surrounds the minority of neoplastic cells, the so-called Hodgkin-Reed Sternberg (HRS) cells. Several studies have shown that HRS cells and cells in the reactive infiltrate produce multiple chemokines. Especially TARC (CCL17) and MDC (CCL22) are highly produced by HRS cells. Altered serum chemokine levels might be related to HL prognosis or disease activity, since immunological mechanisms are crucial in HL pathogenesis. So far, only TARC and IL-8 levels have been studied in the serum of HL patients. In this study serum levels of nine chemokines including, Eotaxin, Fractalkine, IP10, MCP1, MDC, Mig, MIP1a, RANTES, and TARC were examined in serum of 163 untreated HL patients and 334 healthy controls using ELISA. In a subset of nine patients we also examined serum chemokine levels after treatment. Serum levels of TARC and MDC were significantly increased in 82% and 57% of the HL patient group compared to 12% and 5% in the control group, respectively. Serum Fractalkine and Mig levels did not show a difference between patients and controls, whereas serum levels of Eotaxin, IP10, MCP1, MIP1a, and RANTES were significantly decreased in HL patients. Analysis of the different subtypes revealed that the Nodular Sclerosis (NS) cases contained increased serum TARC and MDC levels compared to the Mixed Cellularity (MC) cases (p-value= 0,000). Serum TARC levels strongly correlated with serum MDC levels (r=0.82, p<0.01). Of the nine patients with serum samples before and after treatment, seven showed decreased serum TARC and MDC levels after treatment. One patient with increased levels before treatment did not show decrease in chemokine levels after treatment and died of disease. The last patient did not have increased chemokine levels before treatment and showed similar low levels in both serum samples. The other chemokines did not show a difference in serum levels in the before and after treatment samples. This is the first study testing a broad set of chemokines in serum of HL patients. Of all chemokines tested, TARC and MDC were the only chemokines with increased serum levels in the vast majority of HL patients and these can be used to monitor treatment efficiency.
The TNF Receptor, CD40 Enters Nucleus through Nuclear Pore Complex and Interacts with c-Rel in Aggressive B Cell Lymphoma.
Authors: Zhou Hai-Jun , Pham Lan V. , Tamayo Archito T. , Lin-Lee Yen-Chiu , Fu Lingchen , Yoshimura Linda C. , Ford Richard J. 
Published: October 2019

Abstract
CD40 is a member of TNF receptor family, which plays important roles in the proliferation, survival and differentiation of lymphocytes. Constitutively active CD40 signaling is one of the hallmarks of aggressive B cell lymphoma development and mediates pivotal functions through its downstream pathways, involving NF-kBs. Recently, our group has reported the nuclear localization of CD40, opening a new paradigm in the functional role of CD40 in non-Hodgkin lymphomas of B cell origin (NHL-B). In this study, we show that CD40 co-localizes and immuno-precipitates with nuclear pore complex (NPC) proteins, which suggests NPC proteins are involved in the classic karyopherin pathway that facilitates the nuclear translocation of CD40 protein. Importantly, our co-immunoprecipitation assays and confocal microscopy have demonstrated that, in NHL-B cells, nuclear localized CD40 interacts with the NF-kB protein-c-Rel, but not p65. Chromotin-IP assay further indicates that CD40 forms complexes with c-Rel on the promoters of several proliferation and survival genes-CD154, Blys/BAFF and Bfl-1/A1 in various NHL-B cell lines. Co-transfection of CD40 and c-Rel in NHL-B cells synergistically enhance Blys promoter-driven luciferase activity while CD40 and p65 do not show such synergy. In normal B cells, transfection of c-Rel has synergistically enhanced the proliferation of B lymphocyte after CD40 ligand stimulation, which results in accumulation of CD40 in the nucleus. Furthermore, co-transfection of c-Rel and wild type CD40 also synergizes the proliferation of NHL-B cells, while co-transfection of c-Rel and nuclear localization signal (NLS) mutated CD40 does not. This study suggests that the nuclear CD40 plays an important role in lymphoma growth and survival mechanisms through its interaction with c-Rel, an oncogene that is amplified in many cases of NHL-B that may contribute to the pathophysiology of the disease process. Modulating the nuclear function of CD40 could provide a new targeted therapeutic approach for lymphoma therapy.
Pre-Clinical Development of Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat ™) for the Treatment of Pediatric Acute Leukemias.
Authors: DeRyckere Deborah , Garrington Timothy P. , Gore Lia 
Published: October 2019

Abstract
Acute leukemia is the most common malignancy of childhood and despite a good outcome for the majority of patients, a proportion of patients has high-risk features, and a very poor prognosis for ultimate cure. As such, novel approaches to therapy and new agents are clearly needed to improve the efficacy and quality of treatment available. We are investigating the utility of several histone deacetylase inhibitors (HDACIs) in the treatment of pediatric acute leukemias. Two HDACIs, suberoylanilide hydroxamic acid (SAHA, Vorinostat™) and MS-275, exhibited broad spectrum anti-tumor activity against a panel of 12 pediatric ALL and 8 AML cell lines representing different cell lineages and stages of development, with clinically achievable IC50 values of approximately 200–900nM. Both agents induced apoptosis in a dose-dependent manner. However, SAHA and MS-275 had differential effects on cell cycle progression and differentiation. Treatment with MS-275 resulted in sustained accumulation of cells in G1 phase and cell line-specific changes in the expression of multiple hematopoietic differentiation markers, including HLA-DR, CD11b, CD13, CD33, and CD61. Differentiation of both AML and ALL cell lines was induced. In contrast, treatment with SAHA either had no effect on cell cycle distribution or caused a transient arrest in G1 phase, which was reversible within 24–48 hours. In addition, only minimal changes in the expression of defined hematopoietic differentiation markers were observed following treatment with SAHA. These data suggest that the anti-leukemia effects mediated by SAHA and MS-275 occur by different biochemical and cellular mechanisms. Consistent with this hypothesis, SAHA and MS-275 exhibited synergistic anti-leukemic activity in vitro in a sequence dependent-manner, with a mean combination index of 0.666 +/− 0.048 based on median effect analysis. Sequence-dependent synergy was noted in a variety of T-cell and pre-B cell lines, including cell lines possessing MLL translocations. Both SAHA and MS-275 exhibited synergistic interactions with drugs representing the topoisomerase II, DNA methyltransferase, and proteosome inhibitor classes based on median effect analysis and/or the universal response surface approach. Detailed data demonstrating the mechanism(s) of HDACI-mediated anti-leukemic synergy and sequence-dependence with these other agents will be presented.