bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCL6 Programs Lymphoma Cells for Survival and Differentiation through Distinct Biochemical Mechanisms, Both of Which Can Be Therapeutically Targeted.
Authors: Parekh Samir , Polo Jose , Juszczynski Przemyslaw , Lev Paola , Ranuncolo Stella , Cattoretti Georgio , Shaknovich Rita , Shipp Margaret , Melnick Ari 
Published: October 2019

Abstract
The BCL6 transcriptional repressor is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCL). Constitutive expression of BCL6 has been proposed to mediate lymphomagenesis through several mechanisms, including evasion of cell death, proliferation and differentiation blockade. We show here that BCL6 mediates these effects through distinct mechanisms. First, we show that blocking the association of the SMRT corepressor with BCL6 using our specific peptide inhibitor (BPI) abrogates only the survival effects of BCL6 but has no effect on differentiation. Accordingly, BPI upregulates survival genes such as ATR and p53, but not genes associated with differentiation such as Blimp1, XBP and Syndecan. In contrast, BCL6 shRNA upregulates both survival and differentiation genes and induces both cell death and differentiation. We and others have shown that BCL6 can also directly bind to the MTA3 corepressor, which is implicated in differentiation of Burkitt lymphoma cells. We found that BCL6 and MTA3 are co-expressed in DLBCL cells and primary human centroblasts (the precursor cell for most DLBCLs). The endogenous BCL6 and MTA3 proteins interacted in DLBCLs cells in co-immunoprecipitation experiments. In contrast to SMRT blockade with BPI, siRNA depletion of MTA3 induced expression of the Blimp1, XBP and Syndecan but not p53 and ATR. MTA3 depletion induced plasmacytic differentiation within 72 hours as shown in functional assays and by surface markers. We performed ChIP on chip using custom arrays densely tiling with oligonucleotides covering the entire genomic loci of 20 BCL6 target genes. Interestingly, BCL6 formed different types of repression complexes at differentiation genes (Complex with MTA3/NuRD) vs. survival genes (complex with SMRT and N-CoR). BCL6-mediated repression of genes involved in survival and differentiation thus depend on distinct biochemical mechanisms. The relevance of these findings for human disease was underscored by the fact that we found a statistically significant positive correlation between MTA3 and BCL6 gene expression in a database of 176 human DLBCLs (p&lt;0.00001). Likewise, protein expression of BCL6 and MTA3 was also highly correlated (p&lt;0.00001) (74 cases examined) and staining for Blimp1 revealed mutually exclusive expression from MTA3. Taken together these results illustrate the basic mechanisms through which BCL6 mediates DLBCL lymphomagenesis and provide the basis for powerful targeted therapy regimens that could be translated to the clinical setting.
DNA Methylation Inhibitors Upregulate MiRNA Expression in Patients with Chronic Lymphocytic Leukemia.
Authors: Yu Margaret K. , Mendell Joshua T. , Glenn Martha G. , Chen Zhong , Jones Kimberly A. , Phillips John D. 
Published: October 2019

Abstract
Chronic lymphocytic leukemia is a disease with a variable outcome. Since early treatment does not result in a survival benefit, clinicians often wait for evidence of progressive disease before offering systemic chemotherapy. We recently reported on the contribution of DNA methylation to disease progression. CLL patients with higher than age-expected global DNA methylation demonstrated a requirement for chemotherapy within 12 months as compared to patients with lower than age expected levels. We hypothesized that treatment of patients with early Rai Stage CLL can delay progression of disease by re-expression of tumor suppressor genes. We used two different DNA methylation inhibitors: a DNA methyltransferase enzyme inhibitor, 5-azacytidine, and a methyl substrate inhibitor, 2-chloro-2-deoxyadenosine. We demonstrate increased microRNA expression in six patients treated with 5-azacytidine and the one patient treated with 2-chloro-2-deoxyadenosine. In 6 out of 7 patients, DNA methylation globally decreased by 8% after treatment. However, consistent microRNA upregulation was seen in mir-17-3p, mir-21, mir-29a, mir-29b, mir-29c, mir-30e, mir-104, mir-126, mir-128a, mir-130a, mir-141, mir-142-3p, mir-148a, mir-151, mir-199a, mir-199a*, and mir-301 by real-time PCR using the Early Access Human Panel from Applied Biosystems. Using the University of California Santa Cruz genome database, mir-17, mir-126, mir-128a, mir-148a, mir-151, mir-199a, and mir-301 are sequence conserved in at least 5 mammalian species and are associated with a CpG island upstream from the predicted transcriptional start site. All but mir-148a are embedded within a known gene. No changes were seen in bcl-2, p53, mir-15, or mir-16. Overexpression of mir-199-a and mir-199a* has been shown to induce cell cycle arrest. Mir-17-3p and mir-21 have anti-apoptotic properties. MiRNAs in patients with CLL are likely regulated by DNA promoter methylation.
High CLIP (Class II Associated Invariant Chain Peptide) Expression on Minimal Residual Disease Cells Is Associated with High Relapse Rate in AML Patients.
Authors: Chamuleau Martine E. , Feller Nicole , Kelder Angel , Van de Loosdrecht Arjan A. , Ossenkoppele Gert J. 
Published: October 2019

Abstract
MHC class II molecules are able to present tumor antigens to CD4+ T cells which play in their turn an important role in orchestrating the anti-tumor immune response. MHC class II molecules are only able to present antigen when the antigen binding site has been liberated from CLIP, which is a remnant of the intracellular chaperone molecule called Invariant Chain. Impaired MHC class II antigen presentation by persistent expression of CLIP on the antigen binding site of > 35% of the leukemic myeloid cells at diagnosis of AML patients is correlated to shorter overall survival (Chamuleau et al, Cancer Res.2004; 64:5546–5550). In this study, we investigated the CLIP expression on minimal residual disease (MRD) cells in the bone marrow of patients who achieved complete remission after chemotherapeutic treatment. Such expression may reveal the role of immune control in the outgrowth of MRD cells towards a relapse. The presence of MRD was measured by leukemia associated phenotype (LAP) expression (e.g. expression of the lymphoid cell marker CD7 or natural killer cell marker CD56 on myeloid blasts). Such aberrancies can be defined on AML blasts at diagnosis. At first, we established the percentage of MRD cells of 19 patients who remained in continuous complete remission (median follow up 44 months, range 7.4–109 months, sample taken at median 21 months after complete remission) and of 15 patients who relapsed soon after samples were taken (median time before relapse occurred: 5.9 months, range 1.4–20 months). The median frequency of MRD cells in relapsing patients was 0.1% (range 0.01 – 3.1%) compared to 0.02% (range 0.01–0.09%) in patients who remained in continuous remission. Differences were significant (p=0.017, Mann-Whitney U), in line with our previous finding that a high MRD cell frequency correlates with a high relapse rate (N. Feller et al, Leukemia2004, 18:1380–1390). Furthermore, we established the CLIP expression on the CD34+ LAP+ cells of both groups. Patients that relapsed showed a significant higher median CLIP expression (69%, range 6–96%, SD 27) than the patients that remained in continuous complete remission (median CLIP expression of 31.6% (range 5–93%, SD 26)) p=0.012 (Mann-Whitney U). In a logistic regression analysis both parameters were independent factors for predicting relapse (p=0.014 for CLIP expression and p=0.035 for MRD frequency). In conclusion, the impaired immunogenicity of low frequency MRD cells in patients that are morphologically in complete remission seems to play an important role in the outgrowth of MRD to relapsing leukemia. Enhancing the immunogenicity of MRD cells by restoration of the MHC class II antigen presentation pathway could offer new possibilities for immune therapy of AML patients.
The Role of C-KIT Mutations in the Leukemogenesis of Core-Binding Factor Acute Myeloid Leukemia: A Comparative Analysis on Paired Diagnosis and Relapse Samples.
Authors: Liang Der-Cherng , Shih Lee-Yung , Huang Chein-Fuang , Chang Ya-Tzu , Li Huei-Ying , Lai Chang-Liang 
Published: October 2019

Abstract
C-KIT is a member of the type III receptor tyrosine kinase family and plays a crucial role in normal hematopoiesis and acute myeloid leukemia (AML). C-KIT mutations have been described in core-binding factor (CBF) AML at initial diagnosis. The role of C-KIT mutations in the relapse of CBF AML is not clear. In the present study, we analyzed C-KIT mutations on paired diagnosis and relapse samples in CBF AML. Among 1014 adults and 162 children with AML, CBF AML was detected in 11.4% of adults and 25.3% of children. Mutational analysis of C-KIT was performed by direct sequencing for all cDNA PCR products amplified with 5 overlapping primer pairs, which cover the whole coding sequences of C-KIT gene from exon 1 through exon 21. In AML with t(8;21)/AML1-ETO, 33.0 % (29/88) of adults and 44.4 % (12/27) of children had C-KIT mutations. In AML with inv(16)/CBFβ-MYH11, 22.2 % (6/27) of adults and 38.5 %(5/13) of children had C-KIT mutations. Taken together, C-KIT mutations were present in 30.4 % (35/115) of adults and 42.5 % (17/40) of children with CBF AML. Forty-two patients with CBF AML relapsed. Twenty-two(18 adults and 4 children) of the 23 patients with CBF AML and C-KIT(+) at diagnosis had relapse samples available for comparative analysis. All the 22 patients relapsed with C-KIT mutations, 21 of them showed the identical C-KIT mutation patterns as those at diagnosis. Of the 20 relapsed patients with t(8;21)/AML1-ETO and C-KIT(+), 3 had mutations in exon 8: T417_D419delinsY, Y418_D419delinsA, and [Y418N;Y418_D419insFF], respectively; one had mutation in exon 9: I478V; another one had mutation in exon 11: [D572_P573insL; E561_D572dup]; 14 had mutations in exon 17: 5 D816V, 3 N822K, 3 D816Y, and one each with D816H, D820G, and D820Y; the remaining one patient relapsed twice, the patterns of C-KIT mutations changed but remained in exon 17: D816A at diagnosis, D816V at the first relapse, and N822K at the second relapse. Genotyping analysis with 15 loci of short tandem repeats at 13 different chromosomes showed identity for the diagnosis and the two relapse samples. Of the 2 adults with inv(16)/CBFβ-MYH11 and C-KIT(+) who relapsed, both had mutations in exon 17: N822K and D816Y, respectively. C-KIT mutations were absent in all of the 35 complete remission samples examined. In those with CBF AML and C-KIT(−) at diagnosis, 19 patients including 16 adults and 3 children relapsed; C-KIT mutations were not present in all the relapse samples except one who acquired D816H mutation. The present study showed that all patients with de novo CBF AML harboring C-KIT mutations at diagnosis retained the mutations at relapse, indicating that C-KIT mutations play a crucial role in the leukemogenesis in a substantial proportion of patients with CBF AML.
AML with 11q23/MLL Abnormalities: A Survey of 146 Cases from French AML Intergroup.
Authors: Banos Anne , Jaquet Antoine , Dombret Herve , Auvrignon Anne , Dastugue Nicole , Castaigne Sylvie , Leblanc Thierry , Fenaux Pierre , Rigal-huguet Francoise , Witz Francis , Blaise Didier , Reiffers Josy , Leverger Guy , Harousseau Jean-luc , Socie Gerard , Fiere Denis , Lioure Bruno , Bastard Christian , Thomas Xavier , Lamy Thierry , Pigneux Arnaud 
Published: October 2019

Abstract
Karyotype is one of the most important prognosis factor in acute myeloid leukemia. The MLL gene, located at 11q23, is fused to a variety of partner genes through chromosomal translocations and generates the critical leukemogenic fusion proteins. We performed a large retrospective study in 146 adults and children with 11q23/MLL + rearrangement enrolled in 6 clinical trials conducted in France between 1987 and 1998. Prognosis studies were performed in the 110 patients (47 adults and 63 children) who achieved a complete remission. Individual data were registred, including age, blood and marrow count, extramedullary disease and cytogenetics. The kaplan-Meier method was used in survival analysis and the cox proportinal-hazards model was used to analyse the effect of potential prognosis factors on survival. Among 47 adults, 43 % (20/47) carried t(9 ;11), 19% (9/47) carried t(6 ;11), 23% (11/47) carried t(11 ;19), 6% (3/47) carried t(10 ;11) and 8% (4/47) carried another abnormalities involved 11q23/MLL. Estimated 5-year disease-free survival (DFS), overall survival (OS) and relapse rate (RR) were respectively 17%, 21% and 77%. We analysed separately all translocations involved MLL and we found that the only translocation indicating a favorable prognosis was the translocation t(11 ;19). Compared with other translocations involving MLL, the estimated 5-year DFS, OS and RR of patients with a t(11 ;19) were respectively 45 vs 8% (p=.02), 54 vs 11% (p=.006) and 48 vs 84% (p=.04). Relative risk of relapse was 0,29 (95% confidence interval, 0.09 to 0,9 ;p=.03). Among 63 children, 63% (40/63) carried t(9 ;11), 3% (2/63) carried t(6 ;11), 8% (5/63) carried t(11 ;19), 14% (9/63) carried t(10 ;11) and 11% (7/63) carried another MLL rearrangement. Estimated 5-year DFS, OS and RR were respectively 59%, 72% and 36%. Compared with other translocations involving MLL, we found no difference in outcome between patients with t(9 ;11) and those with other rearrangement of MLL. In conclusion, the most common recurrent abnormality in this large study was translocation t(9 ;11) in adults and children. We found that adults patients whose leukemic cells contained the t(11 ;19) have a better outcome compared with those whose leukemic cells contain other 11q23 /MLL alterations. In children, we do not confirm the favorable impact of t(9 ;11) suggested in previous reports.
B Cell Lymphomas Are Resistant towards Bone Morphogenetic Protein (BMP) Induced Growth Inhibition.
Authors: Huse Kanutte , Eide Marianne B. , Kersten Christian , Smeland Erlend B. , Myklebust June H. 
Published: October 2019

Abstract
Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily, and mediate their effects mainly through the Smad signalling pathway. Whereas TGF-β is well established as one of the most potent negative regulators in hematopoietic cells, the role of BMPs remains more elusive. We have previously shown that BMP-6 inhibits the growth of naïve and memory human B cells. As high BMP-6 mRNA expression is associated with poor outcome in diffuse large B cell lymphoma (DLBCL; Rosenwald et al, N Engl J Med 2002), we hypothesized that resistance towards BMP-induced growth inhibition is a possible mechanism for lymphomagenesis. In the current study, 7 B cell lymphoma cell lines (representing Burkitt lymphoma (BL) and DLBCL) and tumour material from lymphoma patients were investigated to unravel the role of BMPs in lymphomas. We analyzed the expression of BMP receptors by FACS analysis, and found variable expression of the BMP receptor type I (Alk2, Alk3 and Alk6) and type II (BMP RII, Activin RIIA and RIIB) among the cell lines and in primary lymphoma cells, suggesting variable binding of BMPs. We next investigated the effect of BMP-2, BMP-4, BMP-6 and BMP-7 on proliferation and survival of B lymphoma cell lines, and found 2 of 7 cell lines to be resistant towards BMP-2 and BMP-4 induced growth inhibition. In contrast, 4 of 7 and 7 of 7 cell lines were resistant to BMP-6 and BMP-7 induced growth inhibition, respectively. In Sudhl6 cells that were highly sensitive to BMP-2 and BMP-6 induced apoptosis and inhibition of proliferation, we demonstrated that the cytokines IL-10, CD40 Ligand and BLyS were able to counteract the negative effects induced by BMPs, while IL-2 and IL-4 were not. On the contrary, both BMP-2 and BMP-6 greatly increased anti-IgM activation induced apoptosis. In resistant lymphoma cells, the BMPs were not able to induce detectable levels or induced low levels of phosphorylated SMAD1/5/8 compared to sensitive cell lines. Low or no increase in phosphorylation of SMAD1/5/8 induced by BMPs could only partly be explained by low/ undetectable expression of BMP receptors. Hence, upregulation of inhibitory Smads (Smad6, Smad7) or mutations in receptors or Smads represent other possible mechanisms for resistance to BMPs in lymphomas, and this is currently under investigation. We also investigated if the lymphoma cells produced BMPs themselves and found that 5 of 7 cell lines and 3 of 5 primary lymphomas produced significant amounts of BMP-7. Some lymphoma cells also had detectable levels of BMP-4 and BMP-6. Our findings that lymphoma cells are resistant towards BMP-7 and to some degree BMP-6 induced growth inhibition, whereas they produce these cytokines, suggest that resistance towards BMP induced signalling in B cell lymphomas can contribute to increased tumour growth.
Value of FDG-PET in Prediction of Splenectomy Findings in Patients with Suspected or Known Lymphoma.
Authors: Rutherford Sarah C. , Andemariam Biree , Philips Shibu M. , Chadburn Amy , Furman Richard R. , Coleman Morton , Goldsmith Stanley J. , Leonard John P. 
Published: October 2019

Abstract
Splenectomy is frequently performed for diagnostic purposes in patients with suspected or known lymphoma, including assessment for possible transformation. The ability to predict splenectomy findings (and potentially avoid associated morbidity and mortality) would be valuable. The purpose of this study was to determine whether preoperative18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results correlate with pathologic diagnosis from splenectomy.
Methods: One hundred sixty-five patients who had undergone a splenectomy at New York Presbyterian Hospital from January 2004 to July 2006 were identified from the pathology database. Records of these patients were searched and 11 with suspected or known lymphoma as an indication for splenectomy and who had a pre-splenectomy PET scan were identified. A nuclear medicine physician performed a blinded review and assigned each PET scan to one of the following categories based on splenic FDG standardized uptake values (SUV): low splenic metabolic activity (correlated with maximum SUV range 2-3.7), intermediate splenic metabolic activity (maximum SUV range 6–7), and high splenic metabolic activity (maximum SUV range 26–29). Findings were correlated with splenectomy pathologic diagnosis.
Results: Subjects (n=11, 4 female, 7 male) had a median age of 48 years (range 21–72); four had suspected lymphoma pre-splenectomy, while 7 had a prior diagnosis and had splenectomy for diagnostic (to rule out transformation) or other purposes. Median time between PET and splenectomy was 1.25 months. Of 5 patients with low metabolic activity on PET; three had benign findings at splenectomy and two had splenic involvement of previously known mantle cell lymphoma. Three patients had intermediate metabolic activity on PET; all subsequently demonstrated marginal zone lymphoma at splenectomy. Three patients had high metabolic activity on PET; all were found to have diffuse large B cell lymphoma at splenectomy.
Conclusions: This study to our knowledge comprises the largest series to evaluate splenic FDG-PET uptake in patients with suspected or known lymphoma, followed by subsequent pathologic confirmation. Patients with low splenic SUVs appear to be less likely to have splenic involvement of lymphoma, while intermediate and high values may correlate with lymphoma histology. Our findings support a potential role for FDG-PET as a tool for use, in conjunction with clinical and laboratory assessment, in consideration of the need for splenectomy in these settings.
Banoxantrone (AQ4N), a Tissue Targeted Prodrug: Results of a Phase 1 Study in Lymphomas.
Authors: Furman Richard R. , Bartlett Nancy L. , Wong Alvin F. , McCulloch Leanne M. , Lam Gilbert N. , Rosenthal Todd , Flinn Ian , Leonard John P. 
Published: October 2019

Abstract
AQ4N is a prodrug which is selectively bioreduced by cytochrome P450 to AQ4, a potent DNA intercalator and topoisomerase II inhibitor. Preclinical studies demonstrate AQ4N selectively targets lymphoblastoid cell lines and hypoxic tumors. This study assessed the maximum tolerated dose (MTD), and pharmacokinetics (PK) of repeated dosing of AQ4N in patients (pts) with lymphoid malignancies. AQ4N was administered IV on Day 1 of a 21 day cycle to cohorts of at least three pts at doses of 400, 800, or 1200 mg/m2 for a maximum of 8 cycles. The dose was escalated as long as <33% of pts did not experience a dose limiting toxicity (DLT). 11 pts were enrolled with 3 pts treated at 400 mg/m2 and 4 pts treated at 800 and 1200 mg/m2 each. No pts experienced a DLT and no clinical MTD was identified. No further dose escalation was investigated due to reaching known maximum AQ4N solution solubility. The most common related adverse events (AE) observed were expected transient skin discoloration (100%), transient chromaturia (36%) and lymphopenia (27%), as well as fatigue (27%) and nausea (27%). AEs were primarily mild (Grade 1–2) with the exception of Grade 3 lymphopenias (n=3) and Grade 3 neutopenia (n=1) events. No dose reductions or dose delays resulted from these hematologic decreases. 6 pts experienced at least one serious AE, including: pneumonia, staph aureus bacteremia, acute respiratory distress syndrome (ARDS), dyspnea, and pleural effusion, none of which were attributed to AQ4N. The PK was linear over all doses studied. At 1200 mg/m2 (n=4), the Day 1 AQ4N Cmax was 122.3 ± 13.1 μg/mL, AUC0–∞ was 340.8 ± 68.7 μg·h/mL, and T1/2 was 3.2 h (range 2.8 to 4.1 h). One pt with follicular lymphoma dosed at 1200 mg/m2 had a partial response after the 4th cycle using the NHL standardized response criteria. The pt went on to complete all 8 cycles and to date remains in partial response. The bioreductive prodrug, AQ4N, is well-tolerated when administered on a repeated 21-day schedule at doses up to and including 1200 mg/m2. Further dose escalation was precluded since the known maximum solubility of AQ4N was reached. Blood levels of AQ4N achieved in this study appear to be within the range of potentially therapeutic levels of the active drug, AQ4, as seen in previous preclinical and clinical studies of solid tumors (Harris PA et al, 2006; Albertella MR et al., 2006). Preliminary evidence of anti-tumor activity was seen in one pt with follicular lymphoma. Further clinical studies of AQ4N administered both as a monotherapy and in combination with chemo- and radiation therapy are planned in B-cell neoplasms and solid tumor malignancies.