scholarly journals Expanded Populations of Surface Membrane Immunoglobulin Light Chain–Negative B Cells in Lymph Nodes Are Not Always Indicative of B-Cell Lymphoma

2005 ◽  
Vol 124 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Xian-Feng Zhao ◽  
Sindhu Cherian ◽  
Rachel Sargent ◽  
Raja Seethala ◽  
Hugh Bonner ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Light Chain ◽  
Cell Lymphoma ◽  
Surface Membrane ◽  
B Cell Lymphoma ◽  
Immunoglobulin Light Chain ◽  
Membrane Immunoglobulin

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.

Diffuse Large B Cell Lymphoma without Immunoglobulin Light Chain Restriction by Flow Cytometry

2009 ◽  
Vol 121 (4) ◽  
pp. 196-201 ◽  
Author(s):  
Naoto Tomita ◽  
Kengo Takeuchi ◽  
Rie Hyo ◽  
Chizuko Hashimoto ◽  
Sachiya Takemura ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cell ◽  
Light Chain ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immunoglobulin Light Chain ◽  
Light Chain Restriction ◽  
Large B Cell Lymphoma ◽  
Large B Cell

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 Aggressive B-Cell Lymphoma with Dual Surface Immunoglobulin Light-Chain Expression

2007 ◽  
Vol 46 (17) ◽  
pp. 1458-1461 ◽  
Author(s):  
Tohru Fujiwara ◽  
Kenichi Ishizawa ◽  
Katsura Kohata ◽  
Joji Yamamoto ◽  
Minami F Yamada ◽  
...  
Keyword(s):  
B Cell ◽  
Light Chain ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immunoglobulin Light Chain ◽  
Surface Immunoglobulin ◽  
Aggressive 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 Functional immunoglobulin light chain genes are replaced by ongoing rearrangements of germline V kappa genes to downstream J kappa segment in a murine B cell line.

1989 ◽  
Vol 170 (1) ◽  
pp. 1-13 ◽  
Author(s):  
S Levy ◽  
M J Campbell ◽  
R Levy
Keyword(s):  
B Cell ◽  
Light Chain ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intermediate Step ◽  
Immunoglobulin Light Chain ◽  
Additional Mechanism ◽  
Heavy Chains ◽  
Cell Clones ◽  
Parental Tumor

A murine B cell lymphoma (38C13) was subjected to immunoselection with mAbs directed against the idiotypic determinants of its cell surface Ig. Variants emerged with altered Ig receptors containing identical heavy chains but different light chains. The functional light chain genes in these variants were composed of V kappa segments drawn from the V kappa Ox-1 family, which had replaced the V kappa gene expressed by the parental tumor by rearranging to downstream J kappa segments. Rearrangement at the kappa locus continued to occur spontaneously, giving rise to secondary and tertiary variants at a rate of 1.9 x 10(-4) per cell per generation. Variants were isolated that had ceased production of surface Ig but went on to rearrange again and to become surface Ig+. The Ig- state may be an intermediate step providing a stimulus for continued rearrangement. This process provides an additional mechanism for generating diversity within B cell clones and expands the use of the available repertoire of Ig genes.

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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