scholarly journals Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

2016 ◽  
Vol 113 (46) ◽  
pp. 13168-13173 ◽  
Author(s):  
Virginia A. Carroll ◽  
Mark K. Lafferty ◽  
Luigi Marchionni ◽  
Joseph L. Bryant ◽  
Robert C. Gallo ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Microarray Analysis ◽  
Intracellular Signaling ◽  
Matrix Protein ◽  
B Cell Lymphoma ◽  
Viral Proteins ◽  
Increased Risk ◽  
Hiv 1

HIV-1 infection is associated with increased risk for B-cell lymphomas. How HIV infection promotes the development of lymphoma is unclear, but it may involve chronic B-cell activation, inflammation, and/or impaired immunity, possibly leading to a loss of control of oncogenic viruses and reduced tumor immunosurveillance. We hypothesized that HIV structural proteins may contribute to lymphomagenesis directly, because they can persist long term in lymph nodes in the absence of viral replication. The HIV-1 transgenic mouse Tg26 carries a noninfectious HIV-1 provirus lacking part of the gag-pol region, thus constituting a model for studying the effects of viral products in pathogenesis. Approximately 15% of Tg26 mice spontaneously develop leukemia/lymphoma. We investigated which viral proteins are associated with the development of leukemia/lymphoma in the Tg26 mouse model, and performed microarray analysis on RNA from spleen and lymph nodes to identify potential mechanisms of lymphomagenesis. Of the viral proteins examined, only expression of HIV-1 matrix protein p17 was associated with leukemia/lymphoma development and was highly expressed in bone marrow before disease. The tumor cells resembled pro-B cells, and were CD19+IgM−IgD−CD93+CD43+CD21−CD23−VpreB+CXCR4+. Consistent with the pro-B-cell stage of B-cell development, microarray analysis revealed enrichment of transcripts, including Rag1, Rag2, CD93, Vpreb1, Vpreb3, and Igll1. We confirmed RAG1 expression in Tg26 tumors, and hypothesized that HIV-1 matrix protein p17 may directly induce RAG1 in B cells. Stimulation of human activated B cells with p17 enhanced RAG1 expression in three of seven donors, suggesting that intracellular signaling by p17 may lead to genomic instability and transformation.

scholarly journals Dual Conditional Loss of BLIMP-1 and p53 in B-Cells Drives B-Cell Lymphomagenesis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4169-4169
Author(s):  
Antonio Sacco ◽  
Yawara Kawano ◽  
Michele Moschetta ◽  
Jihye Park ◽  
Oksana Zavidij ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Southern Blotting ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Whole Exome ◽  
Btk Inhibitor

Abstract Background. p53 is a well defined tumor suppressor involved in the modulation of cell proliferation, cell cycle progression and programmed cell death. BLIMP-1 plays a crucial role in modulating B-cell differentiation towards Ig-secreting plasma cells, and it acts as a tumor suppressor, as documented in both diffuse large B-cell lymphoma and Burkitt lymphoma. Whether B-cell specific loss of both p53 and BLIMP-1 may favor a B-cell lymphoma phenotype remains unanswered. We therefore aimed to generate in vivo dual p53/BLIMP-1-floxed conditional inactivation in B-cells, and to define the functional relevance of both p53 and BLIMP-1 n B-cell lymphomagenesis in vivo Methods.Cre recombinase under the control of CD19 promoter (C57BL/6 CD19Cre/Cre) mice were crossed with either C57BL/6 BLIMPflox/flox or C57BL/6 p53flox/flox mice to achieve deletion of BLIMP or p53, respectively, in B cells. Secondly, CD19Cre/Cre BLIMPflox/flox mice were crossed with CD19Cre/Cre p53flox/flox to achieve concomitant deletion of both BLIMP and p53 in B cells (CD19Cre/Cre BLIMPflox/flox p53flox/flox), referred as CD19/Bl-/p53- mice. Transgenic experimental mice (CD19/Bl-/p53-) where characterized for B cell infiltration using immunohistochemistry, flow cytometry; clonotypic immunoglobulin heavy-chain rearrangement was assessed by Southern Blotting. Whole exome sequencing was performed using DNA isolated from B220+ selected cells obtained from pathological lymph nodes of CD19/Bl-/p53- mice and from matched tail-derived tissues, used as germline (Illumina HiSeq 2500 platform; Agilent SureSelectXT). MTT assay was used to BTK-inhibitor-dependent cytotoxicity using CD19/Bl-/p53-derived B220 cells. Results.We generated dual p53/BLIMP-1-floxed conditional inactivation in B-cells, using mice expressing Cre recombinase under the control of CD19 promoter. 100% of the CD19/Bl-/p53- mice presented with diffuse lymphadenomegalies, and splenomegaly, hepatomegaly (90.3% and 77.4%, respectively). Other clinical manifestations included presence of ascites and hind lymb paralysis (12.9% and 19.3%, respectively). The CD19/Bl-/p53- showed worse survival compared to Bl-/p53- mice non-expressing the CD19/Cre recombinase, CD19/p53-, or CD19/Bl- (363, 469.5, 460.5, and 770 days, respectively). H.E. staining of CD19/Bl-/p53--derived lymph nodes, defined a nodal architecture with a monomorphic population of large sized atypical lymphoid cells with finely clumped and dispersed chromatin, and multiple basophilic medium sized, paracentrally situated nucleoli. A "starry sky" pattern was also observed. Overall, these features are compatible with a high-grade lymphomas. IHC analysis confirmed a marked positivity for B220 staining (TdT, Bcl6, CD138 and CD4, CD8 negative). Tumors were confirmed to be B220+/IgM+, with either Igk- or Ig-lambda-restriction as demonstrated by flow cytometry; and either mono- or bi-clonal, as demonstrated by Southern blotting, thus further confirming the clonal transformation induced by dual BLIMP/p53 deletion in B cells. Whole exome sequencing was performed from B220+ selected cells obtained from pathological lymph nodes of CD19/Bl-/p53- mice and identified 143 SNVs. Among them, non-synonymous somatic mutations were mapped on genes involved in the regulation of focal adhesion, PDGF signaling, p53-downstream pathway, and lipoprotein metabolism. B220+ cells selected from CD19/Bl-/p53--derived lymph nodes were implanted subcutaneously into recipient SCID/Bg mice (n: 10), and presented with 100% engraftment, with a monomorphic lymphoid infiltration of B220+ and IgM+ cells. B220 positive cells were selected from the s.q. tumor and intravenous injected into recipient SCID/Bg (n: 10) and BL/6 mice (n: 10). Engraftment was demonstrated in all the mice, where hepatomegaly, splenomegaly and hind lymb paralysis were observed. Infiltration of B220+ cells was documented within bone marrow, liver and spleen. We next investigated the anti-tumor activity of BTK-inhibitor, and found that B220+ cells selected from lymph nodes harvested from CD19/Bl-/p53-mice were sensitive to ibrutinib treatment. Conclusion. These studies demonstrate that the specific dual inactivation of p53 and BLIMP in B-cells promotes oncogenic transformation, resulting in aggressive B-cell lymphoma development. Disclosures Ghobrial: Celgene: Other: Advisory Board; BMS: Other: Advisory Board; Amgen: Other: Advisory Board; Takeda: Other: Advisory Board; Janssen: Other: Advisory Board. Roccaro:Takeda Pharmaceutical Company Limited: Honoraria.

scholarly journals HIV-1 Tat Activates Akt/mTORC1 Pathway and AICDA Expression by Downregulating Its Transcriptional Inhibitors in B Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 1588
Author(s):  
Burkitkan Akbay ◽  
Diego Germini ◽  
Amangeldy K. Bissenbaev ◽  
Yana R. Musinova ◽  
Evgeny V. Sheval ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Intracellular Signaling ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Cytidine Deaminase ◽  
Tat Protein ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Hiv 1

HIV-1 infects T cells, but the most frequent AIDS-related lymphomas are of B-cell origin. Molecular mechanisms of HIV-1-induced oncogenic transformation of B cells remain largely unknown. HIV-1 Tat protein may participate in this process by penetrating and regulating gene expression in B cells. Both immune and cancer cells can reprogram communications between extracellular signals and intracellular signaling pathways via the Akt/mTORC1 pathway, which plays a key role in the cellular response to various stimuli including viral infection. Here, we investigated the role of HIV-1 Tat on the modulation of the Akt/mTORC1 pathway in B cells. We found that HIV-1 Tat activated the Akt/mTORC1 signaling pathway; this leads to aberrant activation of activation-induced cytidine deaminase (AICDA) due to inhibition of the AICDA transcriptional repressors c-Myb and E2F8. These perturbations may ultimately lead to an increased genomic instability and proliferation that might cause B cell malignancies.

P-A6 Expression of HIV-1 matrix protein p17 and correlation with B cell lymphoma in HIV-1 transgenic mice

2017 ◽  
Vol 74 ◽  
pp. 73
Author(s):  
Virginia Carroll ◽  
Mark Lafferty ◽  
Luigi Marchionni ◽  
Joseph Bryant ◽  
Robert Gallo ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
B Cell ◽  
Matrix Protein ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hiv 1

scholarly journals Genetic Loss of NFAT2 Leads to CLL Transformation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 364-364
Author(s):  
Melanie Märklin ◽  
Jonas Heitmann ◽  
Felicia Truckenmüller ◽  
Lothar Kanz ◽  
Sebastian Jonas Saur ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Western Blotting ◽  
Calcium Imaging ◽  
B Cell Lymphoma ◽  
Calcium Flux ◽  
Cell Phenotype ◽  
Resting Cells ◽  
Aggressive Disease

Abstract NFAT is a family of highly phosphorylated proteins residing in the cytoplasm of resting cells. Upon dephosphorylation by calcineurin, NFAT proteins translocate to the nucleus where they orchestrate developmental and activation programs in diverse cell types. CLL is a clonal disorder of mature B cells characterized by the expression of CD19, CD23 and CD5. With respect to prognosis, it constitutes a heterogeneous disease with some patients exhibiting an indolent course for many years and others progressing rapidly and requiring early treatment. While some patients exhibit enhanced responsiveness to stimulation of the B cell receptor (BCR) complex and more aggressive disease, another subset of CLL patients with more indolent course is characterized by an anergic B cell phenotype referring to B cell unresponsiveness to IgM ligation and essential lack of phosphotyrosine induction and calcium flux. Up to 10% of CLL patients transform to an aggressive form of lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here, we analyzed the role of NFAT2 in CLL with respect to maintenance of the anergic phenotype and the development of Richter´s syndrome. For this purpose, we generated conditional NFAT2fl/fl CD19-Cre knock out mice on the Eµ-TCL1 transgenic background. These mice exhibit NFAT2 deletion limited to the B cell lineage and develop a human-like CLL due to the B cell specific expression of the TCL1 oncogene. Conditional TCL1+NFAT2fl/fl CD19-Cre mice with B cell specific deletion of NFAT2 served as the experimental cohort while TCL1 transgenic mice without an NFAT2 deletion served as controls. To extend our observations do the human disease, we further analyzed primary blood samples from patients with CLL (n=30) and Richter´s syndrome (n=5). Mice with genetic loss of NFAT2 in their B cell compartment showed a significantly more aggressive disease course with accelerated accumulation of CD5+ CD19+ CLL cells in different organs, significantly higher proliferation rates and a dramatically reduced life expectancy (200 vs. 325 days) as compared to TCL1 control animals. Immunohistochemical analysis of spleen and lymph nodes upon necropsy showed a transformed disease phenotype in the NFAT2 ko cohort with diffuse distortion of lymph node and spleen architecture by large B cells with blastic chromatin while animals with intact NFAT2 expression showed small lymphocytic infiltrates with conserved B and T cell areas as expected. Using calcium imaging technology, we were able to show that CLL cells with regular NFAT2 expression were essentially unable to mobilize calcium upon IgM ligation and thus exhibited the typical anergic phenotype. CLL cells with NFAT2 deletion, on the contrary, showed a highly IgM-responsive phenotype with inducible activation of downstream signaling via AKT and ERK. We subsequently defined a genetic signature of anergy in CLL cells employing Affymetrix microarrays consisting of Lck, Pacsin1 and the E3 ligases Cbl and Grail, which were highly expressed in anergic CLL cells with normal NFAT2 expression and virtually absent upon NFAT2 ablation. We could further show by western blotting with phospho-specific antibodies that Lck was constitutively activated in anergic CLL cells while it was essentially inactive in NFAT2 ko cells suggesting an important role for Lck in mediating the anergic phenotype. Primary human CLL samples (n=30) showed a significant overexpression of NFAT2 and Lck, predominantly in its active conformation, as assessed by western blotting and RT-PCR. Tissue samples (lymph nodes, bone marrow) from patients with Richter's Syndrome (n=4) on the other hand demonstrated a significantly reduced expression of NFAT2 and complete loss of Lck expression. Calcium imaging revealed that a subset of human CLL cells showed an anergic phenotype and were unable to flux calcium while tumor cells from Richter patients exhibited an intensive spontaneous calcium flux as well as hyperresponsiveness upon IgM ligation. In summary, our data provide strong evidence that NFAT2 and its target gene Lck are important mediators of anergy induction in CLL and that their loss leads to disease transformation to aggressive B cell lymphoma (Richter´s syndrome). Taken together, our results demonstrate that the NFAT2-LCK axis plays an important role in the pathogenesis of CLL and implicate it as a potential target in its treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Rituximab efficiently depletes B cells in lung tumors and normal lung tissue

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 38 ◽  
Author(s):  
Albane Joly-Battaglini ◽  
Clara Hammarström ◽  
Branislava Stankovic ◽  
Henrik Aamodt ◽  
Johan Stjärne ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Lung Tissue ◽  
Lung Tumor ◽  
B Cell Lymphoma ◽  
Normal Lung Tissue ◽  
Normal Lung ◽  
Lymphoid Tissues

Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab.

scholarly journals A Rare Case of T-Cell Histiocyte Rich Large B-Cell Lymphoma of the Thyroid in a Patient With Hashimotos

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A879-A880
Author(s):  
Abir Zainal ◽  
Jhansi Maradana ◽  
Mira Torres
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Thyroid Gland ◽  
Lymph Nodes ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare form of large B-cell lymphoma, which usually involves the lymph nodes exclusively. We describe a patient with Hashimoto’s thyroiditis who was discovered to have THRLBCL arising from the thyroid. Clinical Case: A 78-year-old female with a history of Hashimoto’s thyroiditis noted increase in the size of her left thyroid lobe for two months despite normal TSH on Levothyroxine, prompting an ultrasound which revealed several enlarged left sided cervical lymph nodes and an enlarged left thyroid gland. Cytology from an FNA of a left level 3 lymph node showed atypical lymphoid infiltrate featuring scattered large atypical cells in a background of small lymphocytes. Immunohistochemical testing was PAX5+, CD30- and CD15-. Cytology from an FNA of left thyroid revealed identical changes and immunohistochemistry demonstrated PAX5+ and CD20+. Concurrent flow cytometric studies demonstrated increased CD4 to CD8 ratio among T cells. Excisional biopsy of a left cervical lymph node confirmed a diagnosis of THRLBCL. PET/CT exhibited lymphadenopathy above her diaphragm and splenic involvement. Her bone marrow biopsy was negative for involvement. She was deemed Stage III with international prognostic index (IPI) of 2 corresponding with low-intermediate risk. She was commenced on chemotherapy R-CHOP with plan to complete 6 cycles. Discussion: THRLBCL is characterized by scattered atypical B lymphocytes on a background of T lymphocytes and histiocytes. Usually, T-cells are predominantly CD8+, in contrast to our patient. Some studies identified cases of predominant CD4+ and PD1+ T cells. Cytology revealed scattered small B-cells and large B-cells, a feature that is not typically seen in THRLBCL. A diagnosis of diffuse transformation of nodular lymphocyte predominant Hodgkin lymphoma was considered but the diffuse proliferation outside of CD21+ and involvement of the thyroid is not compatible with such diagnosis. Similarly, a diagnosis of follicular helper T-cell lymphoma with admixed large B-cells was considered but while PD1+ CD4+ T cells are present, there was no aberrant antigen expression by flow cytometry or T cell clonality. THRLBCL mainly involves lymph nodes and presents at advanced Ann Arbor stages with high IPI. Malignant lymphomas of the thyroid gland are exceedingly rare, accounting for 2% of thyroid cancers, out of which the literature reveals a single case report of THRLBCL arising from the thyroid. THRLBCL represents an aggressive form of lymphoma and is treated according to stage-matched DLBCL, although the effects of Rituximab in this population is variable. Conclusion: Hashimoto’s is considered a risk for thyroid lymphoma usually diffuse large B-cell lymphoma and MALT lymphoma. We present a rare case of THRLBCL occurring in the setting of Hashimoto’s with acute thyroid gland enlargement.

scholarly journals The Role of CXCL13 in Antibody Responses to HIV-1 Infection and Vaccination

2021 ◽  
Vol 12 ◽  
Author(s):  
Yonas Bekele Feyissa ◽  
Francesca Chiodi ◽  
Yongjun Sui ◽  
Jay A. Berzofsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
B Cell Lymphoma ◽  
Cell Trafficking ◽  
Broadly Neutralizing Antibodies ◽  
G Protein Coupled ◽  
Hiv 1

CXCL13 signals through the G protein-coupled chemokine receptor CXCR5 to drive development of secondary lymphoid tissue as well as B cell and Tfh cell trafficking to germinal centers (GC), which leads to the differentiation of B cells to plasma cells and memory B cells. CXCL13 has been proposed as a general plasma biomarker for GC activities. In HIV-1 infected individuals, plasma CXCL13 levels have been associated with the rate of disease progression to AIDS. Moreover, CXCL13 production has been reported to be increased in HIV-1-infected lymph nodes, which may drive increased downregulation of CXCR5. In this review, we address the role of CXCL13 in HIV-1 infected individuals with regard to GC formation, generation of broadly neutralizing antibodies after infection and vaccination, and AIDS-related B cell lymphoma.

PRDM11 Is a Novel Putative Tumor Suppressor In Aggressive B Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1002-1002
Author(s):  
Fazila Asmar ◽  
Cathrine Kolster Fog ◽  
Klaus Jensen ◽  
Linda Jacobsen ◽  
Elisabeth Ralfkiær ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
Expression Levels ◽  
Immunohistochemistry Staining ◽  
Pr Domain

Abstract Abstract 1002 Introduction and Aim: Deregulation of epigenetic factors contributes together with genetic alterations to the development of cancer. The PR domain proteins (PRDMs) constitute a sub-family of the SET domain family of histone methyl transferases and consist of 17 family members. Several of the PRDMs have been characterized as tumorsuppressors, including PRDM2, PRDM3, PRDM5 and PRDM16, but the mechanisms are largely unknown. In a functional screen with overexpressed MYC, we found that shRNA mediated down regulation of PRDM11 facilitates oncogenic transformation. Given the importance of MYC in lymphoma development it is essential to understand the genetic settings that facilitate MYC-induced transformation. We thus set out to investigate the function of PRDM11 in lymphomagenesis. Methods: To identify PR/SET proteins collaborating with MYC in cellular transformation a retroviral vector based library of shRNA targeting 61 SET and PR domain genes from mice and humans was generated. Primary mouse embryo fibroblasts (MEFs) were transduced with the library and with the Myc overexpression vector. A conditional Prdm11 knockout (KO) mouse strain and crosses to the Eμ-Myc tumor prone strain were generated to evaluate the tumorsuppressor potential of Prdm11 in vivo. The expression levels of PRDM11 in B cell lymphoma cell lines were evaluated by RT-qPCR and immunohistochemistry staining. PRDM11 expression level in Diffuse Large B Cell Lymphoma (DLBCL) patients was assessed by immunohistochemistry staining of DLBCL tissue microarrays (TMAs) according to the H-score. In order to investigate whether the PRDM11 expression was regulated by epigenetic mechanisms we performed H3K27me3 and H3K4me3 ChIP analysis and DNA methylation specific melting curve analysis. DGGE mutation scanning was applied to analyze 17 lymphoma cell lines and 77 DLBCL patients for point mutations. Results: We found that overexpression of Prdm11 in MEFs diminished growth and induced apoptosis in a manner independent of p53 and the intrinsic apoptotic pathway. Furthermore, Prdm11 (KO) MEFs grew faster than their wildtype (WT) littermate controls and transformed in the presence of oncogenic Myc. Prdm11 KO mice were viable and fertile with no apparent phenotype. The Eμ-Myc mice selectively express the Myc transgene in the B-cell lineage and develop malignant lymphomas with a mean latency of 100–120 days. Importantly, we found that loss of Prdm11 potently accelerated lymphomagenesis in the Eμ-Myc mouse (p<0,0006) and induced the incidence time from 111 to 75 days. To investigate the function if PRDM11 in humans, PRDM11 expression levels were evaluated in a panel of human DLBCL and Mantle Cell Lymphoma (MCL) cell lines. Compared to normal B-cells and reactive lymph nodes, PRDM11 mRNA expression levels were significantly lower or absent in 16/19 lymphoma cell lines. PRDM11 immunohistochemistry staining of DLBCL TMAs showed lower levels compared to reactive lymph nodes. PRDM11 immunohistochemistry staining in reactive lymph nodes was mainly localized to the activated B cells in the germinal centres. Interestingly, low or absent PRDM11 expression is associated with significantly worse overall survival (p = 0,011, univariate analysis of 22 patients). We are currently in the process of investigating the prognostic significance of PRDM11 expression in another 100 patients with DLBCL. These data will be presented at the meeting. We have found an inverse correlation between the expression level of PRDM11 and the presence of the repressive chromatin mark H3K27me3 at the PRDM11 promoter by ChIP analysis. H3K27me3 is less enriched at the promoter of PRDM11 in normal B cells as well as in cell lines with EZH2 missense mutation. DNA methylation was not detected in 17 lymphoma cell lines or 77 DLBCL patients and 3 PRDM11 sequence variants were also present in the germ line. In conclusion: PRDM11 is a novel putative tumor suppressor in mice and men, whose downregulation may be associated with poor prognosis in DLBCL. H3K27 trimethylation of the PRDM11 promoter may be a novel target for therapy in DLBCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Epigenetic suppression of SLFN11 in germinal center B cells in the process of the dynamic expression change during B-cell development

2020 ◽  
Author(s):  
Fumiya Moribe ◽  
Momoko Nishikori ◽  
Hiroyuki Sasanuma ◽  
Remi Akagawa ◽  
Hiroshi Arima ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Germinal Center ◽  
Cytosine Arabinoside ◽  
Immunohistochemical Staining ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Epigenetic Modifiers ◽  
Anti Cancer

<strong>Background</strong>   SLFN11 enhances cellular toxicity of genotoxic anti-cancer agents, and its important role under physiological conditions has not been appreciated yet. Somatic hypermutations and class switch recombination that can cause physiological genotoxic stress arise in germinal center B cells (GCBs). GCBs are a major origin of B-cell lymphomas that are frequently treated by cytosine arabinoside, a genotoxic anti-cancer agent.   <strong>Objective</strong>   To clarify the expression profile of <em>SLFN11</em> in different stages of B cells and B-cell lymphomas.   <strong>Methods</strong>   We analyzed the expression of <em>SLFN11</em> by mining publicly available databases for different stages of normal B cells and various types of B-cell lymphoma lines and also by performing immunohistochemical staining of human lymph nodes. We investigated the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on <em>SLFN11</em> expression in B-cell lymphoma lines and examined the therapeutic efficacy of these epigenetic modifiers in the combination with cytosine arabinoside.   <strong>Results</strong>   <em>SLFN11 </em>expression was specifically low in GCBs compared to non-GCBs, which was consolidated by the immunohistochemical staining for SLFN11 with human lymph nodes. <em>SLFN11</em> expression levels in B-cell lymphoma lines largely correlated to those of their normal counterparts. The epigenetic modifiers upregulated <em>SLFN11</em> expression in GCB-derived lymphomas and made the lymphomas further susceptible to cytosine arabinoside.   <strong>Conclusions</strong>   The expression of <em>SLFN11</em> may be epigenetically suppressed in GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low <em>SLFN11</em> expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.

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