scholarly journals Genetic Events Inhibiting Apoptosis in Diffuse Large B Cell Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2167
Author(s):  
Etienne Leveille ◽  
Nathalie Johnson
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
Malignant Cells ◽  
Large B Cell Lymphoma ◽  
Apoptotic Proteins ◽  
Apoptotic Pathways ◽  
Genetic Events ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL) is curable with chemoimmunotherapy in ~65% of patients. One of the hallmarks of the pathogenesis and resistance to therapy in DLBCL is inhibition of apoptosis, which allows malignant cells to survive and acquire further alterations. Inhibition of apoptosis can be the result of genetic events inhibiting the intrinsic or extrinsic apoptotic pathways, as well as their modulators, such as the inhibitor of apoptosis proteins, P53, and components of the NF-kB pathway. Mechanisms of dysregulation include upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins via point mutations, amplifications, deletions, translocations, and influences of other proteins. Understanding the factors contributing to resistance to apoptosis in DLBCL is crucial in order to be able to develop targeted therapies that could improve outcomes by restoring apoptosis in malignant cells. This review describes the genetic events inhibiting apoptosis in DLBCL, provides a perspective of their interactions in lymphomagenesis, and discusses their implication for the future of DLBCL therapy.

scholarly journals Genetic Events Inhibiting Apoptosis in Diffuse Large B-cell Lymphoma

2021 ◽  
Author(s):  
Etienne Leveille ◽  
Nathalie A. Johnson
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
Malignant Cells ◽  
Large B Cell Lymphoma ◽  
Apoptotic Proteins ◽  
Apoptotic Pathways ◽  
Genetic Events ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL) is curable with chemoimmunotherapy in ~65% of patients. One of the hallmarks of the pathogenesis and resistance to therapy in DLBCL is inhibition of apoptosis, which allows malignant cells to survive and acquire further alterations. Inhibition of apoptosis can be the result of genetic events inhibiting the intrinsic or extrinsic apoptotic pathways, as well as their modulators, such as the inhibitor of apoptosis proteins, P53, and components of the NF-kB pathway. Mechanisms of dysregulation include upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins via point mutations, amplifications, deletions, translocations, and influences of other proteins. Understanding the factors contributing to resistance to apoptosis in DLBCL is crucial in order to be able to develop targeted therapies that could improve outcomes by restoring apoptosis in malignant cells. This review describes the genetic events inhibiting apoptosis in DLBCL, provides a perspective of their interactions in lymphomagenesis, and discuss their implication for the future of DLBCL therapy.

scholarly journals Jun-regulated genes promote interaction of diffuse large B-cell lymphoma with the microenvironment

Blood ◽  
2015 ◽  
Vol 125 (6) ◽  
pp. 981-991 ◽  
Author(s):  
Marzenna Blonska ◽  
Yifan Zhu ◽  
Hubert H. Chuang ◽  
M. James You ◽  
Kranthi Kunkalla ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
B Cell ◽  
Stromal Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Matrix Proteins ◽  
Malignant Cells ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Large B Cell

Key Points Elevated Jun signaling promotes lymphoma growth and dissemination to extranodal sites. Jun-regulated genes mediate the interaction of malignant cells with stromal cells and adhesion to extracellular matrix proteins.

The B Cell Receptor Antagonist R406 Alters The Balance Between Anti-Apoptotic and Pro-Apoptotic Signals To Strongly Synergize With ABT-199 In Diffuse Large B Cell Lymphoma Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2538-2538
Author(s):  
Yue Zhang ◽  
Powell Francoise ◽  
Erik Devereaux ◽  
Melissa Passino ◽  
Julie Parmentier ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Clinical Investigation ◽  
Active Form ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Large B Cell Lymphoma ◽  
Apoptotic Proteins ◽  
Large B Cell

Abstract SYK plays an essential role in B cell receptor (BCR) mediated survival in Diffuse Large B Cell Lymphoma (DLBCL). In a previous clinical investigation, fostamatinib, a potent Syk inhibitor, showed evidence of anti-tumour activity with an overall response rate of ∼20% in a cohort of DLBCL patients (JW Friedburg et al Blood. 2010, 115:2578-85). This finding prompted us to investigate the mechanism of action of fostamatinib in DLBCL. Our previous work demonstrated R406, the metabolic active form of fostamatinib, functions as a BCR antagonist in DLBCL cells. Treatment with R406 reduced MCL1 and down-regulated Bfl-1 expression, leading to apoptosis induction in sensitive cells. Due to R406’s impact on apoptosis machinery, here we explored the ability of R406 to combine with a selective Bcl2 inhibitor, ABT-199 in DLBCL cells. Drug combinations were tested in DLBCL cells and synergy scores were determined using a 6x6 dose matrix followed by analysis via Chalice software (Zalicus). ABT-199 strongly synergized with R788, the prodrug of R406, in multiple R406 sensitive, but not resistant cell lines. In contrast, little effect was observed in combinations of R788 with other reagents, including ibrutinib (PCI-32765), bortezomib, CAL-101 and dasatinib. Flow-cytometry apoptosis analysis confirmed that R406 enhanced ABT-199-induced apoptosis in both ABC subtype and GCB subtype DLBCL cells. Further studies demonstrated R406 not only decreased anti-apoptotic proteins, but also activated pro-apoptotic proteins. Specifically, R406 suppressed ERK-dependent phosphorylation of BIM on S69, resulted in stabilization of BIM. In addition, R406 induced dephosphorylation of BAD at S136 in sensitive but not resistant cells, likely through inhibition of AKT kinase activity. Furthermore, treatment of R406 also upregulated other pro-apoptotic BH3-only proteins such as HRK1 and BMF1, which may partially contribute to the observed synergy. In conclusion, we have demonstrated R406 strongly synergizes with ABT-199 in vitro, likely by altering the balance between anti-apoptotic and pro-apoptotic signals in DLBCL cells. This may provide a potential combination therapy to be tested in DLBCL. Disclosures: Zhang: AstraZeneca: Employment, Possible shareholder Other. Francoise:AstraZeneca: Employment, Possible shareholder Other. Devereaux:AstraZeneca: Employment, Possible shareholder Other. Passino:AstraZeneca: Possible shareholder Other. Parmentier:AstraZeneca: Possible shareholder Other. Byth:AstraZeneca: Employment, Possible shareholder Other.

scholarly journals Somatic copy number gains in MYC, BCL2, and BCL6 identifies a subset of aggressive alternative-DH/TH DLBCL patients

2020 ◽  
Vol 10 (11) ◽  
Author(s):  
Jordan E. Krull ◽  
Kerstin Wenzl ◽  
Keenan T. Hartert ◽  
Michelle K. Manske ◽  
Vivekananda Sarangi ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Rearrangements ◽  
Newly Diagnosed ◽  
Copy Number Alterations ◽  
Large B Cell Lymphoma ◽  
Genetic Events ◽  
Large B Cell

Abstract Double/triple hit lymphoma (DH/TH), known as high-grade B-cell lymphoma (HGBL), is an aggressive diffuse large B cell lymphoma (DLBCL), defined as having concurrent MYC, BCL2, and/or BCL6 gene rearrangements. While gene rearrangements represent significant genetic events in cancer, copy number alterations (CNAs) also play an important role, and their contributions to rearrangements have yet to be fully elucidated. Using FISH and high-resolution CNA data, we defined the landscape of concurrent gene rearrangements and copy gains in MYC, BCL2, and BCL6, in a cohort of 479 newly diagnosed DLBCL. We also show that concurrent translocations and copy number alterations, in combinations similar to DH/TH, identify a unique subset of DLBCL, alternative DH/TH, that have survival outcomes similar to DH/TH DLBCL patients.

Determining the Mechanism of Transformation of Follicular Lymphoma into Diffuse Large B Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 181-181 ◽  
Author(s):  
Emanuela Carlotti ◽  
David Wrench ◽  
Sameena Iqbal ◽  
Derville O’Shea ◽  
Andrew Davies ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Precursor Cell ◽  
Specific Primers ◽  
Large B Cell Lymphoma ◽  
Common Precursor ◽  
Genetic Events ◽  
Large B Cell

Abstract The molecular mechanisms involved in histological transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL) are largely unknown. Here we investigated the clonal relationship in FL and DLBCL in 17 cases of paired FL/DLBCL samples and also in a bone marrow transplant (BMT) model. The aim of this study was to determine the cell of origin of the transformed DLBCL (t-DLBCL) and whether this cell always arises as a clonal evolution from the major FL clone. The immunoglobulin variable heavy chain (IgVH) was amplified by PCR using family specific primers, the major clone identified by homo/heteroduplex and genealogical trees generated. As expected 70% of FL/DLBCL cases used VH3, 24% VH4 and 6% VH5. The median degree of somatic hypermutation (SHM) was 15% (range 4 to 43%). In 3/17 cases the pattern of SHM was identical between FL and DLBCL. In 6/17 cases a clear pattern of direct evolution was evident. Surprisingly for 8/17 cases the pattern of SHM was compatible with the FL and DLBCL arising from a precursor cell rather than direct evolution. Clone specific primers and probes were designed to investigate whether there was evidence of the t-DLBCL in the earlier biopsy. Quantification by RQ-PCR demonstrated that in most cases the transformed clonotype was already present at levels between 10-4 and 10-2. We further examined an interesting case in which both the father (donor) and the son (recipient) developed FL and t-DLBCL 3 and 10 years after transplantation respectively. Sequencing confirmed the presence of an identical t(14;18) translocation in donor and recipient and that both cases used IGHV3-48*03. Analysis of the genealogical trees of SHM in these cases was also consistent with the evolution of t-DLBCL from a common precursor cell rather than direct evolution. These data are consistent with two distinct patterns of transformation of FL to t-DLBCL. About 50% of our cases had evidence of direct evolution while in the remaining 50% the pattern is more suggestive of the FL and t-DLBCL arising from a common precursor cell. The long latency period after BMT is in agreement with the requirement for additional genetic events within the t(14;18) bearing post germinal centre precursor lymphoma cell for the development of these diseases. The finding of the t-DLBCL clonotype in the FL sample before transformation suggests that the transforming event may occur in a minor subclone of the disease or earlier in a lymphoma precursor cell. Ongoing experiments seek to investigate the genetic events arising in these cells that result in transformation.

Expression but Not Promoter Hypermethylation of the Tyrosine Phosphatase PTPN6 Is Associated with Activated STAT3 and Inferior Prognosis in Diffuse Large B Cell Lymphoma Molecular Subtypes.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2655-2655
Author(s):  
Mamta Gupta ◽  
Guangzhen Hu ◽  
Steven Offer ◽  
Matthew J Maurer ◽  
Linda Wellik ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Subtypes ◽  
Cell Lymphoma ◽  
Molecular Subtype ◽  
Tyrosine Phosphatase ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
Promoter Hypermethylation ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 2655 Diffuse large B cell lymphoma (DLBCL) has been classified into two distinct molecular subtypes: germinal center B cell–like (GCB), non-germinal centre-like (non-GCB). To improve outcomes for DLBCL patients, it is necessary to identify additional novel targets within GCB and non-GCB classifications to further stratify patients for prognosis and assist in choosing therapy for the individual patient. We have recently demonstrated that STAT3 activation is frequent in the DLBCL tumors, however the exact molecular mechanism(s) of STAT3 activation in DLBCL tumors are not known. Molecular mechanisms such as epigenetic silencing of negative regulators of the STAT3 pathway such as protein tyrosine phosphatase 6 (PTPN6) may contribute to STAT3 activation. We aimed to learn whether PTPN6 was expressed in GCB and non-GCB DLBCL, and if so, how that expression correlated with STAT3 activation and prognosis. We first performed epigenetic studies of PTPN6 in 38 DLBCL tumors and 6 DLBCL cell lines by methylation specific (MSP) PCR and high resolution melting array (HRM) methods. Surprisingly, PTPN6 promoter hypermethylation (0/38) was not detected in patient sample and cell lines by both the methods. Since the MSP PCR technique yields qualitative rather than quantitative data, we next performed pyrosequencing on the 38 DLBCL samples, and found results consistent with the MSP PCR analysis. Our data conclusively demonstrate that PTPN6 hypermethylation is absent in DLBCL tumors. We next sequenced the 600 bp upstream of the transcription initiation site of PTPN6 promoter 2 and 1 in 10 DLBCL tumors. We did not detect any point mutations in the promoter 2 and 1 core regions. Since PTPN6 promoter hypermethylation and mutations were absent in DLBCL tumors, we determined the expression level of the PTPN6 protein in 40 DLBCL tumors by molecular subtype. Formalin fixed paraffin-embedded DLBCL tumor samples were stained by immunohistochemistry (IHC) for the determination of molecular subtype using the Hans algorithm and the detection of PTPN6 expression. Using a threshold of ≥30%, 75% (30/40) of cases were PTPN6 positive with various levels of expression: 11 cases had 30–80% of tumor cells staining positive and 19 had >80% of cells PTPN6 positive. PTPN6 expression by IHC was only correlated with higher IPI scores and a trend towards a shorter event free survival (EFS) (p=0.07). Within the 29 GCB tumors 69% (20/29) were PTPN6 positive; 100% (10/10) of non-GCB cases were PTPN6 positive. These data clearly suggest that PTPN6 expression is found in both GCB and non-GCB with the latter being uniformly positive (p=0.03) and PTPN6 negative cases being uniformly GCB. PTPN6 mRNA and protein was detected in all three ABC lines (LY3, Ly10, DHL2). Within the GCB lines (DHL6, Ly1 and Ly19) DHL6 was weakly positive and Ly1 and Ly19 were negative for PTPN6 mRNA and protein. Furthermore, within the GCB group PTPN6 positive cases had inferior EFS as compared to PTPN6 negative cases. In the non-GCB group all cases were PTPN6 positive with an EFS similar to PTPN6 positive GCB cases. The role of PTPN6 in the persistent activation of the STAT3 pathway in DLBCL patients has not been investigated. We hypothesized that tumors with activated STAT3 would have loss of PTPN6. Interestingly, this hypothesis was disproven. Within the 15-pSTAT3 positive cases 12 (80%) were PTPN6 positive. Conversely, 26% (6/23) of the pSTAT3 negative cases were PTPN6 negative. The distribution of pSTAT3 and PTPN6 by IHC in samples was evaluated in both GCB and non-GCB groups. Within the PTPN6+/pSTAT3+ group out of the 12 cases most were non-GCB (8/12; 66%). However, within the PTPN6-/pSTAT3- group all the 5 cases were GCB (5/5; 100%). Survival analysis revealed that the groups with the best EFS were those with PTPN6-/pSTAT3- tumors (n=5); those with PTPN6+/pSTAT3+ group (n=12) had the shortest EFS; and those with PTPN6+/pSTAT3- tumors (n=17) being intermediate between the other groups. In summary, we have demonstrated for the first time that PTPN6 is highly expressed in DLBCL tumors, and a common abnormality in non-GCB subtypes, which is positively correlated with activated STAT3. PTPN6 expression in the DLBCLs is not regulated through SHP1 promoter hypermethylation or point mutations. The finding that SHP1 loss was found only in GCB cases and was especially favorable should be explored further and may provide an important new stratification factor for future DLBCL studies. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance of BAD and AIF Apoptotic Pathways in Diffuse Large B-Cell Lymphoma

2010 ◽  
Vol 10 (2) ◽  
pp. 118-124 ◽  
Author(s):  
Danielle Troutaud ◽  
Barbara Petit ◽  
Cynthia Bellanger ◽  
Benoît Marin ◽  
Marie-Pierre Gourin-Chaury ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Apoptotic Pathways ◽  
Large B Cell

scholarly journals Defining Immunoglobulin Somatic Hypermutation in De Novo Diffuse Large B-Cell Lymphoma Patients: Potential Application for Prognosis and Risk Stratification

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1669-1669
Author(s):  
Ilan Kirsch ◽  
Zijun Yidan Xu-Monette ◽  
Thomas Snyder ◽  
Ken H. Young
Keyword(s):  
B Cell ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

Abstract Context Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of diseases with variable clinical presentation, morphologic features, genomics, gene expression signature and prognosis. Some of the variability in patient course and response to therapy is likely to represent a function of developmental stage and/or specific pathway of transformation. We have been engaged in a detailed investigation of the molecular and clinical features of a large cohort of patients with DLBCL at the MD Anderson Cancer Center. Through these analyses we have begun to subcategorize this patient population based on these distinctive clinical and biological parameters. In this current aspect of our investigation we have explored the prevalence of somatic hypermutation (SHM) of the immunoglobulin loci in these de novo DLBCL patients using the platform of multiplex PCR and high-throughput sequencing (immunoSEQ) developed by Adaptive Biotechnologies, Inc. It has previously been established that the presence or absence of somatic hypermutation is an independent prognostic factor in patients with chronic lymphocytic leukemia (CLL). The ultimate goal of this collaborative effort is to determine if a similar biological mechanism between somatic hypermutation and prognosis exists within the population of DLBCL patients or subset and to relate the presence of SHM to clinical, pathological, and molecular aspects of this disease. Objective In this study, we investigated whether the immunoSEQ (Adaptive Biotech) assay could be used to reliably discriminate dominant clones in diagnostic specimens from patients with DLBCL with regard to rearrangement status of the immunoglobulin heavy and light (kappa and lambda) chains and the presence or absence of SHM. Patients The study group consisted of 200 DLBCL patients treated with R-CHOP. Patients with primary mediastinal large B-cell lymphoma, primary cutaneous DLBCL, primary central nervous system DLBCL, and DLBCLs transformed from a low-grade B-cell lymphoma or associated with HIV infection were excluded. Methods Genomic DNA was extracted from FFPE sections of diagnostic lymph node specimens of patients with DLBCL. Immunoglobulin heavy and light chain sequences were then independently amplified using multiplex PCR with optimized primer sets. Following high-throughput sequencing, a bioinformatics pipeline clusters the sequences into distinct clonotypes to determine overall frequencies and to identify diagnostic clones. V, (D,) and J genes are also identified for each clonotype, and point mutations that are not known germ-line allele variants are assigned as somatic hypermutation events. Results Using both the IgH and IgL (kappa and lambda) we have been able to identify an index trackable sequence in 90%+ of the samples (we identify an index diagnostic sequence or sequences in about 70% of the cases using each assay individually). Using a definition of SHM as >2% point mutations in the observed V gene, the samples can be split into three distinct categories: 1, V(D)J or VJ rearranged with SHM (50-55%); 2, V(D)J or VJ rearranged without SHM (10-25%) and 3, DJ only evident (20-40%) The vast majority of complete V(D)J rearrangements are in-frame. Conclusions The IgH and IgL immunoSEQ assays are robust in their ability both to identify dominant sequences in diagnostic lymph node specimens from patients with DLBCL and to distinguish those clones in which evidence of somatic hypermutation is present. The distribution of SHM in these samples lends itself to potential correlative and stratifying analyses on this well-characterized patient cohort, and likely have significant application in other aggressive B-cell lymphoma patients. Disclosures Kirsch: Adaptive Biotechnologies: Employment, Equity Ownership. Snyder:Adaptive Biotechnologies, Inc: Employment, Equity Ownership.

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