BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1599-1607 ◽  
Author(s):  
Ofer Margalit ◽  
Hila Amram ◽  
Ninette Amariglio ◽  
Amos J. Simon ◽  
Sigal Shaklai ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Transcriptional Activation ◽  
P53 Protein ◽  
Genetic Alterations ◽  
Mrna Levels ◽  
Response Element ◽  
Non Hodgkin Lymphoma

The BCL6 transcriptional repressor mediates survival, proliferation, and differentiation blockade of B cells during the germinal-center reaction and is frequently misregulated in B-cell non-Hodgkin lymphoma (BNHL). The p53 tumor-suppressor gene is central to tumorigenesis. Microarray analysis identified BCL6 as a primary target of p53. The BCL6 intron 1 contains a region in which 3 types of genetic alterations are frequent in BNHL: chromosomal translocations, point mutations, and internal deletions. We therefore defined it as TMDR (translocations, mutations, and deletions region). The BCL6 gene contains a p53 response element (p53RE) residing within the TMDR. This p53RE contains a motif known to be preferentially targeted by somatic hypermutation. This p53RE is evolutionarily conserved only in primates. The p53 protein binds to this RE in vitro and in vivo. Reporter assays revealed that the BCL6 p53RE can confer p53-dependent transcriptional activation. BCL6 mRNA and protein levels increased after chemotherapy/radiotherapy in human but not in murine tissues. The increase in BCL6 mRNA levels was attenuated by the p53 inhibitor PFT-α. Thus, we define the BCL6 gene as a new p53 target, regulated through a RE frequently disrupted in BNHL.

scholarly journals Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens

Haematologica ◽  
2019 ◽  
Vol 105 (4) ◽  
pp. 1032-1041 ◽  
Author(s):  
Anna Vidal-Crespo ◽  
Alba Matas-Céspedes ◽  
Vanina Rodriguez ◽  
Cédric Rossi ◽  
Juan G. Valero ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Anti Tumor Activity

HSP105 Inhibition Counteracts Key Oncogenic Pathways and Hampers the Growth of Human Aggressive B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1562-1562
Author(s):  
Roberta Zappasodi ◽  
Alessandra Cavanè ◽  
Monica Tortoreto ◽  
Cristina Tringali ◽  
Giusi Ruggiero ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Lentiviral Vector ◽  
Tumor Formation ◽  
Aggressive Lymphoma ◽  
Proliferation Index ◽  
Immunodeficient Mice ◽  
Non Hodgkin Lymphoma

Abstract Abstract 1562 Our previous findings have made it clear that the significant clinical efficacy attained by dendritic cell-based vaccination in relapsed B-cell non-Hodgkin lymphoma (B-NHL) patients is firmly associated with multifaceted immunologic responses, including the development of anti-heat shock protein (HSP)105 humoral immunity (Di Nicola et al., Blood 2009 113:18–27; Zappasodi et al., Cancer Res. 2010 70:9062–9072; Zappasodi et al., Blood 2011 118:4421–4430). Human HSP105 is a high-molecular-weight chaperone constitutively expressed at low levels within the cytoplasm, and can also be induced in the nucleus by various forms of stress. It is overexpressed in several solid tumors, including melanoma, breast, thyroid and gastroenteric cancers. We have recently shown that this is also true for B-NHLs, in which HSP105 levels increase in function of their aggressiveness and proliferation index (Zappasodi et al., Blood 2011 118:4421–4430). Accordingly, in normal lymph nodes HSP105 expression is confined to the hyper-proliferating germinal center (GC) B cells, suggesting its involvement in the potentially oncogenic GC reactions. We have now set out to clarify the functional role of HSP105 in B-NHLs by stably silencing its expression in the Namalwa aggressive lymphoma cell line. Namalwa cells were infected by using a lentiviral vector carrying a HSP105-targeting pre-microRNA sequence and the Emerald Green Fluorescent Protein (EmGFP) gene, both under the human cytomegolovirus immediate early promoter, as well as the blasticidin resistance gene. Control cells were mock-infected with the empty vector. Infected cells were initially selected in the presence of blasticidin, and then single GFP+ cells were sorted on a flow cytometry device. In this way, we achieved 100% GFP+ subclones that displayed a specific constitutive down-regulation of HSP105, as there was no significant decrease in the expression of its cognate molecular homolog HSP70, or the other major cellular chaperone HSP90. Comparison of the in vitro proliferation rate of two silenced clones with that of the mock culture showed that the cell doubling time of both clones significantly increased and their in vitro growth was accordingly delayed (P= 0.01 and P= 0.04). Western blot analysis in 6 different silenced clones of the oncoproteins most frequently involved in B-NHLs revealed that BCL-6 and c-Myc were down-regulated in function of HSP105 knockdown levels, whereas in mock cells no modifications were detected with respect to their wild-type counterparts. Further strengthening the association between HSP105, BCL-6 and c-Myc expression, immunohistochemistry analysis of 50 primary human aggressive B-NHLs revealed that HSP105 expression, measured both as intensity and percentage of positive cells, was significantly higher in c-Myc- or BCL-6-dependent Burkitt (P= 0.0264) and diffuse large B-cell lymphomas (P= 0.0068) respectively than in other aggressive istotypes that do not overexpress these oncoproteins. These findings support the potential pro-tumorigenic cooperation of HSP105 with BCL-6 and c-Myc transcription factors. To find out whether counteracting HSP105 functions hampers in vivo lymphoma growth, we evaluated the tumor-forming capability of HSP105-silenced (siHSP105) or mock Namalwa cells subcutaneously injected into severe combined immunodeficient mice at serial 10-fold dilutions from 106 to 104 cells/injection (Figure 1). We found that HSP105 knockdown slightly delayed in vivo Namalwa tumor formation when 106 and 105 cells were injected. Noteworthy, no lesions appeared over 70-day observation in mice inoculated with 104 siHSP105 cells, whereas palpable tumors were present in 67% of the animals 24 days after injection of the mock cells (Figure 1). Overall, these results indicate that HSP105 may be a per se nononcogenic molecule that contributes to lymphomagenesis by facilitating the tumorigenic functions of key oncoproteins. They equally provide the rationale for developing HSP105 inhibitors as a novel strategy for improving the treatment of aggressive B-NHLs. Figure 1. In vivo tumor-forming capability of siHSP105 or mock Namalwa cells Figure 1. In vivo tumor-forming capability of siHSP105 or mock Namalwa cells Disclosures: Gianni: Hoffmann-La Roche: Consultancy, Honoraria.

scholarly journals Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2508-2516 ◽  
Author(s):  
Ryan M. Young ◽  
Ian R. Hardy ◽  
Raedun L. Clarke ◽  
Nicolai Lundy ◽  
Polly Pine ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Mouse Models ◽  
Tumor Regression ◽  
Nonreceptor Tyrosine Kinase ◽  
Non Hodgkin Lymphoma ◽  
Pharmacologic Inhibition

We have generated mouse models of non-Hodgkin lymphoma (NHL) that rely on the cooperation between MYC overexpression and B-cell antigen receptor (BCR) signaling for the initiation and maintenance of B-cell lymphomas. Using these mouse models of NHL, we have focused on the identification of BCR-derived signal effectors that are important for the maintenance of NHL tumors. In the present study, we concentrate on Spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase required to transduce BCR-dependent signals. Using a genetic approach, we showed that Syk expression is required for the survival of murine NHL-like tumors in vitro and that tumor cells deficient in Syk fail to expand in vivo. In addition, a pharmacologic inhibitor of Syk was able to induce apoptosis of transformed B cells in vitro and led to tumor regression in vivo. Finally, we show that genetic or pharmacologic inhibition of Syk activity in human NHL cell lines are generally consistent with results found in the mouse models, suggesting that targeting Syk may be a viable therapeutic strategy.

An Fc-Engineered Humanized Anti-CD40 Monoclonal Antibody, XmAb5485, Exhibits Potent Activity in Vitro and in Vivo against Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 881-881 ◽  
Author(s):  
Eugene A. Zhukovsky ◽  
Holly Horton ◽  
Matthias Peipp ◽  
Erik Pong ◽  
Matthew Bernett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Lymphocytic Leukemia ◽  
Non Hodgkin Lymphoma

Abstract CD40, a transmembrane glycoprotein belonging to the tumor necrosis factor receptor family, is an attractive target for cancers of lymphoid origin since it is expressed on most mature B-cell malignancies, some early B-cell acute lymphocytic leukemias, and multiple myeloma. Finding efficient therapies for multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and rituximab-refractory Non-Hodgkin Lymphoma (NHL) represents an unmet need. Several anti-CD40 antibodies, both agonistic and antagonistic, have demonstrated objective responses in early clinical NHL trials and thus validated this antigen as a target for lymphoproliferative diseases. Here we present the characterization of a novel Fc-engineered and humanized anti-CD40 antibody, XmAb®5485, that was generated using our XmAb antibody engineering technology. This antibody is highly cytotoxic against lymphoma, leukemia and multiple myeloma cell lines as well as primary cancer cells. XmAb5485 is characterized by: i) increased affinity for Fc gamma receptors (FcgR), ii) improved effector function, and iii) significantly increased antitumor potency. We investigated several direct and indirect (Fc-mediated) mechanisms of antibody-mediated cytotoxicity in vitro. The potency (EC50) of XmAb5485 in antibody-dependent cell-mediated cytotoxicity (ADCC) increased up to 150-fold relative to the native non Fc-engineered version (anti-CD40 IgG1) of the antibody in a screen of Burkitt’s lymphoma [BL], CLL and MM-derived cell lines. In the same cell lines, ADCC potency and maximal efficacy (% lysis) of XmAb5485 were also superior to that of rituximab: 74- and 1.3-fold higher in CLL, 12.5- and 1.4-fold higher in BL, and 190- and 1.9-fold higher in MM. In a MM cell line with low density of CD40 expression (~3500 per cell) XmAb5485 facilitated efficient ADCC whereas anti-CD40 IgG1 was virtually ineffective. Furthermore, using a BL cell line (Ramos) XmAb5485 displayed antibody-dependent cellular phagocytosis (ADCP) with potency and efficacy increased relative to rituximab (15- and 1.6-fold) and anti-CD40 IgG1 (5- and 1.2-fold). XmAb5485 also exhibited anti-proliferative apoptotic activity that was similar to that of rituximab. Ex vivo, XmAb5485 mediated potent ADCC of multiple primary patient-derived CLL, MCL, and plasma cell leukemia (PCL, an aggressive form of MM) cells, with substantially increased potency and efficacy relative to rituximab; in contrast, anti-CD40 IgG1 displayed minimal or no activity in these primary tumor cells. In vivo, in an established large (210–350 mm3) sc Ramos tumor xenograft model, 6 mg/kg XmAb5485 cured 80% of mice of detectable tumors and displayed statistically significant superiority over anti-CD40 IgG1. In contrast, only 7% of animals in the rituximab cohort were cured. In summary, our data suggest that XmAb5485, an anti-CD40 Fc variant antibody engineered for increased effector function, is a promising next-generation immunotherapeutic for leukemias, lymphomas, and multiple myeloma.

scholarly journals ANTI-TUMOR ACTIVITY OF DARATUMUMAB, A NOVEL HUMAN ANTI CD38 MONOCLONAL ANTIBODY, IN IN VITRO AND IN VIVO MODELS OF B-CELL NON-HODGKIN LYMPHOMA

2017 ◽  
Vol 35 ◽  
pp. 46-47 ◽  
Author(s):  
P. Pérez-Galán ◽  
A. Vidal-Crespo ◽  
A. Matas-Céspedes ◽  
V. Rodriguez ◽  
C. Rossi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
In Vivo Models ◽  
Non Hodgkin Lymphoma ◽  
Anti Tumor Activity

scholarly journals Head-to-head antisense transcription and R-loop formation promotes transcriptional activation

2015 ◽  
Vol 112 (18) ◽  
pp. 5785-5790 ◽  
Author(s):  
Raquel Boque-Sastre ◽  
Marta Soler ◽  
Cristina Oliveira-Mateos ◽  
Anna Portela ◽  
Catia Moutinho ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Promoter Hypermethylation ◽  
Antisense Transcription ◽  
Mrna Levels ◽  
Loop Formation ◽  
Primary Tumors ◽  
Tissue Integrity ◽  
Antisense Knockdown

The mechanisms used by antisense transcripts to regulate their corresponding sense mRNAs are not fully understood. Herein, we have addressed this issue for the vimentin (VIM) gene, a member of the intermediate filament family involved in cell and tissue integrity that is deregulated in different types of cancer.VIMmRNA levels are positively correlated with the expression of a previously uncharacterized head-to-head antisense transcript, both transcripts being silenced in colon primary tumors concomitant with promoter hypermethylation. Furthermore, antisense transcription promotes formation of an R-loop structure that can be disfavored in vitro and in vivo by ribonuclease H1 overexpression, resulting inVIMdown-regulation. Antisense knockdown and R-loop destabilization both result in chromatin compaction around theVIMpromoter and a reduction in the binding of transcriptional activators of the NF-κB pathway. These results are the first examples to our knowledge of R-loop–mediated enhancement of gene expression involving head-to-head antisense transcription at a cancer-related locus.

scholarly journals In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

2014 ◽  
Vol 13 (12) ◽  
pp. 2886-2897 ◽  
Author(s):  
Girija Dasmahapatra ◽  
Hiral Patel ◽  
Johnathan Friedberg ◽  
Steven N. Quayle ◽  
Simon S. Jones ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Proteasome Inhibitor ◽  
Lymphoma Cells ◽  
Non Hodgkin Lymphoma ◽  
Hdac6 Inhibitor

scholarly journals Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 729-739 ◽  
Author(s):  
April Chiu ◽  
Weifeng Xu ◽  
Bing He ◽  
Stacey R. Dillon ◽  
Jane A. Gross ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Myeloid Cells ◽  
Small Interfering Rnas ◽  
Cell Accumulation ◽  
Germinal Center B Cell ◽  
B Cell Precursors

Abstract Hodgkin lymphoma (HL) originates from the clonal expansion of malignant Hodgkin and Reed-Sternberg (HRS) cells. These B-cell–derived elements constitute less than 10% of the tumoral mass. The remaining tissue is comprised of an inflammatory infiltrate that includes myeloid cells. Myeloid cells activate B cells by producing BAFF and APRIL, which engage TACI, BCMA, and BAFF-R receptors on the B cells. Here, we studied the role of BAFF and APRIL in HL. Inflammatory and HRS cells from HL tumors expressed BAFF and APRIL. Unlike their putative germinal center B-cell precursors, HRS cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cells. BAFF and APRIL enhanced HRS cell survival and proliferation by delivering nonredundant signals via TACI and BCMA receptors through both autocrine and paracrine pathways. These signals caused NF-κB activation; Bcl-2, Bcl-xL, and c-Myc up-regulation; and Bax down-regulation, and were amplified by APRIL-binding proteoglycans on HRS cells. Interruption of BAFF and APRIL signaling by TACI-Ig decoy receptor, which binds to and neutralizes BAFF and APRIL, or by small-interfering RNAs targeting BAFF, APRIL, TACI, and BCMA inhibited HRS cell accumulation in vitro and might attenuate HL expansion in vivo.

scholarly journals Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma

Blood ◽  
2017 ◽  
Vol 129 (13) ◽  
pp. 1768-1778 ◽  
Author(s):  
Sophia Gayle ◽  
Sean Landrette ◽  
Neil Beeharry ◽  
Chris Conrad ◽  
Marylens Hernandez ◽  
...  
Keyword(s):  
B Cell ◽  
Anticancer Activity ◽  
Mechanism Of Action ◽  
Kinase Inhibitor ◽  
Lysosomal Function ◽  
Non Hodgkin Lymphoma ◽  
Key Points ◽  
Unique Mechanism

Key Points Apilimod has broad anticancer activity in vitro and in vivo across all subtypes of B-NHL. Apilimod induces B-NHL cytotoxicity through a unique mechanism of action that involves the disruption of lysosomal function.

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