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.

Pathologic Co-Expression and Physical Interaction of c-MYC and BCL6 in B-Cell Lymphomas.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2-2 ◽  
Author(s):  
Masumichi Saito ◽  
Ryan T. Phan ◽  
Herbert C. Morse ◽  
Laura Pasqualucci ◽  
Riccardo Dalla-Favera
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Transgenic Animals ◽  
Primary Lymphoma ◽  
Physical Interaction

Abstract Deregulated expression of the proto-oncogenes BCL6 and c-MYC caused by chromosomal translocation or somatic hypermutation is common in non-Hodgkin B cell lymphoma derived from germinal center (GC) B cells, including diffuse large cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Normal GC B cells express BCL6, whereas, surprisingly, they do not express c-MYC, suggesting that the expression of this oncogene in BL and DLBCL (20% of cases) is ectopic (Klein, U. et al. Proc Natl Acad Sci U S A100, 2639–2644, 2003). Here we report that c-MYC is absent in proliferating GC B cells because it is transcriptionally suppressed by BCL6, as demonstrated by the presence of specific BCL6 binding sites in the c-MYC promoter region and by chromatin immunoprecipitation experiments showing that BCL6 is bound to these sites in vivo. Thus, c-MYC escapes BCL6-mediated suppression in lymphoma leading to the co-expression of the two transcription factors, an event never observed in immunohistochemical and gene expression profile analysis of normal GC B cells. Surprisingly, co-immunoprecipitation experiments and in vitro binding experiments indicate that, when co-expressed, BCL6 and c-MYC are physically bound in a novel complex detectable in DLBCL and BL cell lines as well as in primary lymphoma cases. The formation of the BCL6/c-MYC complex has several significant functional consequences on the function of both c-MYC and BCL6: 1) a two fold, BCL6-binding dependent increase in c-MYC half-life, an event that has been shown to contribute to its oncogenic activation; 2) a synergistic increase in the ability of both BCL6 and c-MYC to suppress MIZ1-activated transcription of the p21CIP cell cycle arrest gene; 3) MYC-dependent inhibition of BCL6 acetylation by p300, an event that physiologically inactivates BCL6 via c-MYC-mediated recruitment of HDAC. Notably, the pathologic co-expression of c-MYC and BCL6 was shown to have pathologic consequences in vivo, since double transgenic BCL6/c-MYC mice display accelerated lymphoma development and the appearance of a novel GC-derived tumor phenotype not recognizable in single transgenic animals and containing the pathologic c-MYC/BCL6 complex. Thus, the pathologic co-expression and illegitimate physical interaction of BCL6 and c-MYC leads to an increase in the constitutive activity of both oncogenes. These results identify a novel mechanism of oncogenic function for BCL6 and c-MYC and a novel tumor-specific protein complex of potential therapeutic interest.

Assessing CD137 (4-1BB) As a Therapeutic Target in B-Cell Neoplasms,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3735-3735
Author(s):  
Adam D Cohen ◽  
Indira D Joshi ◽  
Valentin Robu ◽  
Hossein Borghaei ◽  
Tahseen I. Al-Saleem ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
Tumor Cell ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Cell Proliferation

Abstract Abstract 3735 Agonist monoclonal antibodies (mAbs) to CD137, a co-stimulatory TNF receptor family member expressed on activated T and NK cells, can induce immune-mediated rejection of multiple murine tumor types, and a fully human anti-CD137 mAb, BMS-663513, is in early-phase clinical trials in solid tumors. Significant activity has been seen in murine lymphoma models, both alone and in combination with anti-CD20 mAbs, providing rationale for clinical studies in lymphoma patients. Recently, however, CD137 up-regulation on activated human B cells has been reported, with CD137 ligation causing enhanced B cell proliferation and survival. This raises the concern that mAb binding to CD137, if present, on B cell neoplasms may promote tumor cell proliferation and/or resistance to apoptosis that may counteract the beneficial effects on T and NK cells. We therefore sought to assess the expression of CD137 on a series of human cell lines and primary tumor samples from patients with B-cell neoplasms, and if expressed, to explore the consequences of ligation with the anti-CD137 agonist BMS-66513. First, archived paraffin-embedded lymph node specimens from patients with low-grade B-cell lymphoma (n=11: 5 follicular, 4 marginal zone, 2 small lymphocytic) and diffuse large B-cell lymphoma (n=15) were stained for CD137 by immunohistochemistry. Reactive tonsillar tissue served as a positive control. No CD137 expression was observed within any tumor cells. Next, fresh samples from 14 additional patients with known tumor involvement of peripheral blood or bone marrow (8 chronic lymphocytic leukemia, 1 mantle cell lymphoma, 3 myeloma, 2 marginal zone lymphoma) were analyzed by multi-color flow cytometry. Again, no CD137 expression was observed on the gated neoplastic cells. Baseline surface expression of CD137 was similarly absent in all B cell-derived lines tested (Raji, FCTxFL2, FSCCL, DoHH2, Jeko-1, RPMI8226). However, activation with PMA/Ionomycin could reproducibly induce CD137 expression (% positive: 0.17% → 91%) after 24 hours in 1 of the lines: the follicular lymphoma FSCCL. Interestingly, this was the only line tested that lacked constitutive expression of CD137 ligand (CD137L), suggesting some reciprocal regulation of ligand and receptor expression. Despite this up-regulation of CD137, in vitro ligation of PMA/Ionomycin-activated FSCCL cells with BMS-66513 did not further increase tumor cell proliferation, nor protect the cells from activation-induced cell death, in contrast to effects of CD137 ligation reported in normal B cells (Zhang et al, J Immunol 2010; 184:787). Similarly, BMS-663513 treatment of activated, CD137+ FSCCL cells did not diminish the apoptosis induced by doxorubicin or bortezomib treatment. In addition, FSCCL cells recovered from ascites 7 and 14 days following intraperitoneal injection in SCID mice did not express CD137, implying that CD137 up-regulation is not occurring in vivo during tumor growth. Finally, treatment of FSCCL cells with rituximab, either in vitro or in vivo, did not induce CD137 expression. In conclusion, we demonstrate a lack of steady-state CD137 expression on malignant B cells, confirming the prior study by Houot et al (Blood 2009; 114:3431) and extending these findings to include CLL/SLL for the first time. While CD137 could be induced in a single cell line upon non-specific activation, CD137 expression on FSCCL cells was not seen under physiologic conditions likely to be encountered in the clinical setting, consistent with the primary patient data. Furthermore, even when CD137 was expressed, ligation with the agonist anti-CD137 mAb BMS-663513 did not provide a pro-proliferative or anti-apoptotic signal. These studies provide reassurance and further rationale for exploring agonist anti-CD137 antibodies as therapies for B cell neoplasms. Disclosures: Borghaei: Lilly, Genentech, Amgen, Pfizer: Honoraria, Research Funding. Jure-Kunkel:Bristol Meyers Squibb: Employment.

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 BCL6 Controls the Expression of the B7-1/CD80 Costimulatory Receptor in Germinal Center B Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 211-221 ◽  
Author(s):  
Huifeng Niu ◽  
Giorgio Cattoretti ◽  
Riccardo Dalla-Favera
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Interactions ◽  
Costimulatory Receptor

The BCL6 proto-oncogene encodes a transcriptional repressor required for the development of germinal centers (GCs) and implicated in the pathogenesis of GC-derived B cell lymphoma. Understanding the precise role of BCL6 in normal GC formation and in lymphomagenesis depends on the identification of genes that are direct targets of its transcriptional repression. Here we report that BCL6 directly controls the expression of B7–1/CD80, a costimulatory receptor involved in B–T cell interactions critical for the development of T cell–mediated antibody responses. Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-κB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-κB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. The results suggest that BCL6 may directly control the ability of B cell to interact with T cells during normal GC development. In addition, these findings imply that T–B cell interactions may be disrupted in B cell lymphoma expressing deregulated BCL6 genes.

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.

Development of a Bruton's Tyrosine Kinase (Btk) Inhibitor, ONO-WG-307: Efficacy in ABC-DLBCL Xenograft Model – Potential Treatment for B-Cell Malignancies,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3731-3731 ◽  
Author(s):  
Ryohei Kozaki ◽  
Toshio Yoshizawa ◽  
Shuji Tohda ◽  
Tomoko Yasuhiro ◽  
Shingo Hotta ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Lymphoid Cells ◽  
B Cell Malignancies ◽  
Pharmacodynamic Marker ◽  
Btk Inhibitor

Abstract Abstract 3731 Purpose: ONO-WG-307 is a small molecule inhibitor that covalently binds to Btk. Signals from B cell receptors (BCR) play a central role in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. BCR signaling is implicated in the survival of malignant B cells and recent studies indicate that targeting Btk, an essential component of the BCR pathway, may be effective in the treatment of B-cell lymphoma. The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis and new therapies, preferably chemo-sparing therapies, or as add-on to existing treatment regimens are required to help treat patients with ABC-DLBCL. Therefore, Btk constitutes an interesting therapeutic target, thus the activity of ONO-WG-307 was evaluated in an ABC-DLBCL xenograft model. Methods: Tumor cells (TMD-8) were implanted subcutaneously into female SCID mice. Tumors were allowed to grow to a volume of 100–200 mm3 before the mice were randomized into groups based on tumor size. ONO-WG-307 was administered orally at doses up to 10 mg/kg bid. Tumors were measured two or three times weekly after initiation of treatment, and tumor volumes were determined using the formula volume (=width2xlength)/2. Animals were euthanized when the tumors reached a maximum volume of 2,000 mm3 or after a maximum period of 2 months. In parallel, an exploratory pharmacodynamic marker of Btk inhibition (Phosphorylated-Btk [P-Btk]) was also investigated in vivo. Results: Treatment with ONO-WG-307 resulted in a dose-dependent inhibition of tumor growth in a TMD-8 xenograft model. Furthermore, parallel analysis of a pharmacodynamic marker, P-Btk, supported that Btk was inhibited and the level of P-Btk inhibition was correlated with the decreased tumor volumes observed in the TMD-8 model. Conclusion: ONO-WG-307 is a highly potent and selective oral Btk inhibitor with evidence of efficacy in the ABC-DLBCL xenograft model, with Btk inhibition further supported using a PD marker. Given the need to treat and overcome disease resistance especially in ABC-DLBCL, the use of a Btk inhibitor is a novel, mechanistic approach to treating B cell malignancies. Additional work is underway, combining ONO-WG-307 with chemotherapy and other targeted agents. Disclosures: No relevant conflicts of interest to declare.

scholarly journals In vivo targeting of B-cell lymphoma with glycan ligands of CD22

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4778-4786 ◽  
Author(s):  
Weihsu C. Chen ◽  
Gladys C. Completo ◽  
Darren S. Sigal ◽  
Paul R. Crocker ◽  
Alan Saven ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Treatment Options ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Novel Approach ◽  
Liposomal Nanoparticles

Abstract Antibody-mediated cell depletion therapy has proven to provide significant clinical benefit in treatment of lymphomas and leukemias, driving the development of improved therapies with novel mechanisms of cell killing. A current clinical target for B-cell lymphoma is CD22, a B-cell–specific member of the sialic acid binding Ig-like lectin (siglec) family that recognizes α2-6–linked sialylated glycans as ligands. Here, we describe a novel approach for targeting B lymphoma cells with doxorubicin-loaded liposomal nanoparticles displaying high-affinity glycan ligands of CD22. The targeted liposomes are actively bound and endocytosed by CD22 on B cells, and significantly extend life in a xenograft model of human B-cell lymphoma. Moreover, they bind and kill malignant B cells from peripheral blood samples obtained from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential for using a carbohydrate recognition–based approach for efficiently targeting B cells in vivo that can offer improved treatment options for patients with B-cell malignancies.

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.

scholarly journals CG'806, a First-in-Class Pan-FLT3/Pan-BTK Inhibitor, Exhibits Broader and Greater Potency Than Ibrutinib Against Primary and Cultured Malignant B Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3503-3503
Author(s):  
Hongying Zhang ◽  
Andrea Local ◽  
Khalid Benbatoul ◽  
Peter Folger ◽  
Susan Sheng ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Stromal Cells ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Malignancies ◽  
Apoptotic Effect ◽  
Btk Inhibitor ◽  
Induced Apoptosis

Abstract Mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) account for >70% of cases of B cell lymphoma. Targeting Bruton tyrosine kinase (BTK) with ibrutinib in B cell malignancies led to a paradigm shift in therapy. However, primary resistance to ibrutinib has been observed in about 30% MCL patients; more than 50% patients with CLL and MCL treated with ibrutinib discontinue treatment due to intolerance or emergence of resistant disease (Woyach et al., 2017; Shpilberg et al., 2018). CG'806 is an oral small molecule non-covalent pan-FLT3/pan-BTK inhibitor designed to address the shortcomings of ibrutinib. It is in development for acute myeloid leukemia (AML) and B cell lymphoma. CG'806 inhibited cell proliferation and induced apoptosis with a potency that was 50-6,000 times greater than that of ibrutinib when tested against 14 established malignant B-cell lines in vitro. When tested against 124 samples freshly isolated from the marrow of CLL patients the median IC50 for CG'806 was 0.11 µM and the median for ibrutinib was 4.09 µM, respectively, p<0.001). Since stromal-mediated signaling plays important roles in malignant B cell survival and chemoresistance, the apoptotic effect of CG'806 was further analyzed on cultured and primary malignant B cells in the presence of stromal cells. CG'806 produced similar dose-dependent apoptotic effect on Mino cells, an MCL cell line, in the absence or presence of human stromal HS5 cells indicating that its potency was not impaired by factors released by these stroma cells. Most importantly, CG'806 dose-dependently induced apoptosis in ibrutinib-refractory primary MCL samples in the presence of CD40L-expressing stromal cells (N=4). Whereas 0.1 µM and 1 µM CG'806 caused about 25% and 45% apoptotic cell death, respectively, 1 µM ibrutinib induced less than 10% cell death under the same culture conditions. CG'806 inhibited malignant B cell colony formation and migration towards SDF1α about 2-fold more effectively than ibrutinib. Given the role of activated B cell receptor (BCR) and NFκB pathways in lymphoma, CG'806 was tested for its ability to impair signaling in these pathways. CG'806 produced cell line dependent and dose/time dependent decreases in the phosphorylation of BTK, PLCγ2, PI3K, AKT, mTOR, PKC, and ERK, and reduced. These effects were correlated with induction of PARP cleavage and cell cycle arrest. We conclude that CG'806 inhibits driver and rescue pathways to directly and potently kill a broad range of malignant B cells, including both establish cell lines and freshly isolated patient samples, thereby distinguishing CG'806 from ibrutinib and supporting clinical development of CG'806 in patients with CLL and other B-cell malignancies intolerant, resistant, or refractory to ibrutinib. Disclosures Zhang: Aptose Biosciences, Inc: Employment. Local:Aptose Biosciences, Inc: Employment. Benbatoul:Aptose Biosciences, Inc: Employment. Folger:Aptose Biosciences, Inc: Employment. Sheng:Aptose Biosciences, Inc: Employment. McLaughlin:Aptose Biosciences, Inc: Other: internship. Danilov:Astra Zeneca: Consultancy; Genentech: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Takeda Oncology: Research Funding. Tyner:Constellation: Research Funding; Aptose: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Takeda: Research Funding; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Array: Research Funding. Howell:Aptose Biosciences, Inc: Research Funding. Rice:Aptose Biosciences, Inc: Equity Ownership.

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