scholarly journals Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Tim Pieters ◽  
Sara T’Sas ◽  
Stijn Vanhee ◽  
André Almeida ◽  
Yasmine Driege ◽  
...  
Keyword(s):  
B Cell ◽  
Protease Activity ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Cycle Regulators ◽  
Cyclin D2 ◽  
In Vivo Models ◽  
Pathway Activation ◽  
Effective Therapeutic Strategy

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that hematopoiesis-specific activation of cyclin D2 is sufficient to drive murine MCL-like lymphoma development. Furthermore, we demonstrate that cyclin D2 overexpression can synergize with loss of p53 to form aggressive and transplantable MCL-like lymphomas. Strikingly, cyclin D2–driven lymphomas display transcriptional, immunophenotypic, and functional similarities with B1a B cells. These MCL-like lymphomas have B1a-specific B cell receptors (BCRs), show elevated BCR and NF-κB pathway activation, and display increased MALT1 protease activity. Finally, we provide preclinical evidence that inhibition of MALT1 protease activity, which is essential for the development of early life–derived B1a cells, can be an effective therapeutic strategy to treat MCL.

scholarly journals The Nek2 Genetic Knockout Mouse Model Provides Novel Treatment Strategies in Myeloma and Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5612-5612
Author(s):  
Li Can ◽  
Kalyan Nadiminti ◽  
Yuqi Zhu ◽  
Yogesh Jethava ◽  
Ivana Frech ◽  
...  
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Development ◽  
B Cell Lymphoma ◽  
Cell Tumor ◽  
High Dose ◽  
In Vivo Models

Abstract Background; Major progress in the treatment of B cell tumors has been made in the past decades. Nevertheless, relapses and refractoriness to currently available chemotherapy and even to high dose therapy with stem cell transplantation still cause significant mortality. NEK2, NEver in Mitosis Gene A (NIMA)-Related Kinase 2, is a serine/threonine kinase. High expression of NEK2 increases cell survival and drug resistance, resulting in poor clinical outcome in multiple cancers including multiple myeloma and lymphoma. In this study, we used genetic mouse models to evaluate whether NEK2 is a druggable target in the treatment of B cell tumors including myeloma and diffuse large B-cell lymphoma (DLBCL). Materials and Methods: We have generated Nek2 knockout mice and crossed these with Eµ-Myc mice. RNA-sequencing was performed to determine signaling pathways related to Nek2 inhibition. Both NEK2 and USP7 (a protein interacting with NEK2) inhibitors were applied to treat myeloma and DLBCL in vitro and in vivo. Results: Mouse studies showed that Nek2 played a critical role in B cell tumor development and progression. Specifically, in genetic Eμ-MYC transgenic mice, which spontaneously develop DLBCL and Burkitt lymphoma, knockout of Nek2 prevented B cell tumor development and significantly extended mouse survival. Further, immunohistochemistry analyses showed that Nek2 was highly detected in biopsies from aggressive Burkitt lymphoma patients. Our data also indicate that both NEK2 and USP7 inhibitors significantly inhibited myeloma cell and lymphoma cell growth in vitro and in vivo models and without apparent toxicity to normal tissues. Intriguingly, the combination of USP7 inhibitor P5091 with doxorubicin blocked B cell lymphoma development and extended lymphoma mouse survival. Conclusions: Our studies demonstrate the importance of Nek2 function in tumorigenesis and progression in B cell lineage malignancies. Both NEK2 and USP7 inhibitors showed excellent efficacy in the treatment of myeloma and B-cell lymphoma. Disclosures No relevant conflicts of interest to declare.

A phase I dose-escalation trial of ublituximab (TG-1101), a novel anti-CD20 monoclonal antibody (mAb), for rituximab relapsed/refractory B-cell lymphoma patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8575-8575 ◽  
Author(s):  
Changchun Deng ◽  
Jennifer Effie Amengual ◽  
Marshall T. Schreeder ◽  
Sean Clark-Garvey ◽  
Molly Patterson ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
In Vivo Models ◽  
Anti Cd20

8575 Background: Anti-CD20 therapy (rituximab or RTX) in treating patients (pts) with B-cell lymphomas has resulted in significant improvement in treatment response and clinical outcomes. Despite advances, pts continue to relapse from, or are refractory to, RTX-based regimens. Ublituximab (UTX) is a novel, chimeric mAb targeting a unique epitope on the CD20 antigen. UTX has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, and therefore demonstrates greater ADCC activity than RTX (Le Garff-Tavernier, 2011). UTX displayed greater antitumor activity compared to RTX in NHL in vivo models and in low CD20 expressing tumors (ASH 2011). A phase I trial with UTX used as a single agent in pts with relapsed/refractory CLL reported a response rate of 45%. Herein we report on the phase I dose-escalation of UTX in pts with RTX relapsed/refractory B-cell lymphoma. Methods: Eligible pts have B-cell lymphoma relapsed or refractory to a RTX containing regimen. Pts are required to have measurable/evaluable disease, ECOG PS < 2 and no active hepatitis B/C. The phase I dose-escalation uses a sequential 3+3 design in dose cohorts of 450mg, 600mg and 900mg respectively. UTX is administered once weekly for 4 infusions followed by monthly maintenance therapy. PK and correlative PD data are being collected. Primary endpoint: Maximum Tolerated Dose (MTD) and Dose Limiting Toxicities (DLT). Efficacy is a secondary endpoint. Results: Nine pts (5 FL, 3 MZL, 1 MCL) have been enrolled (3 each cohort). Median age 63; 3/6 (M/F). Median prior Rx = 4 (2-6). RTX refractory (44%). 8/9 pts are evaluable for safety; no DLT’s observed and no Grade 3/4 AE’s to date. 7/9 pts have had at least one response assessment (8 wk scan), which includes: 1 CR (rituximab refractory MZL); 2 PR’s (1 MZL, 1 FL); 2 SD (FL) and 2 PD (1 transformed FL, 1 MCL). PK analysis is ongoing. Conclusions: UTX has been well tolerated to date with no G 3/4 AE’s with demonstrated early clinical activity at all doses. 7/9 patients continue to receive UTX treatment (range 1–25 wks). Enrollment in the 900mg expansion cohort is now open with an emphasis on RTX relapsed/refractory indolent or low CD20-expressing lymphomas. Clinical trial information: NCT01647971.

scholarly journals B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

Blood ◽  
2016 ◽  
Vol 127 (22) ◽  
pp. 2732-2741 ◽  
Author(s):  
Gero Knittel ◽  
Paul Liedgens ◽  
Darya Korovkina ◽  
Jens M. Seeger ◽  
Yussor Al-Baldawi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Specific Expression ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Conditional Expression ◽  
Large B Cell

Key Points B-cell–specific expression of Myd88p.L252P leads to the development of DLBCL in mice. The Myd88p.L252P mutation cooperates with BCL2 amplifications in ABC-DLBCL lymphomagenesis in vivo.

scholarly journals Imaging the mechanisms of anti-CD20 therapy in vivo uncovers spatiotemporal bottlenecks in antibody-dependent phagocytosis

2021 ◽  
Vol 7 (8) ◽  
pp. eabd6167
Author(s):  
Capucine L. Grandjean ◽  
Zacarias Garcia ◽  
Fabrice Lemaître ◽  
Béatrice Bréart ◽  
Philippe Bousso
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Critical Path ◽  
B Cell Lymphoma ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Fluorescent Reporter ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Partial Depletion

Anti-CD20 antibody (mAb) represents an effective strategy for the treatment of B cell malignancies, possibly involving complement activity, antibody-dependent cellular cytotoxicity and phagocytosis (ADP). While ADP by Kupffer cells deplete circulating tumors, mechanisms targeting non-circulating tumors remain unclear. Using intravital imaging in a model of B cell lymphoma, we establish here the dominance and limitations of ADP in the bone marrow (BM). We found that tumor cells were stably residing in the BM with little evidence for recirculation. To elucidate the mechanism of depletion, we designed a dual fluorescent reporter to visualize phagocytosis and apoptosis. ADP by BM-associated macrophages was the primary mode of tumor elimination but was no longer active after one hour, resulting in partial depletion. Moreover, macrophages were present at low density in tumor-rich regions, targeting only neighboring tumors. Overcoming spatiotemporal bottlenecks in tumor-targeting Ab therapy thus represents a critical path towards the design of optimized therapies.

scholarly journals Validation of epigenetic mechanisms regulating gene expression in canine B-cell lymphoma: An in vitro and in vivo approach

PLoS ONE ◽  
2018 ◽  
Vol 13 (12) ◽  
pp. e0208709 ◽  
Author(s):  
Silvia Da Ros ◽  
Luca Aresu ◽  
Serena Ferraresso ◽  
Eleonora Zorzan ◽  
Eugenio Gaudio ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Epigenetic Mechanisms

scholarly journals Apoptosis and in vivo models to study the molecules related to this phenomenon

2010 ◽  
Vol 8 (4) ◽  
pp. 495-497 ◽  
Author(s):  
Adriana Luchs ◽  
Claudia Pantaleão
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Ectopic Expression ◽  
B Cell Lymphoma ◽  
Murine Models ◽  
In Vivo Models ◽  
Large B Cell Lymphoma ◽  
Pathological Conditions ◽  
Pharmacological Targets

ABSTRACT Apoptosis or programmed cell death is a physiological process, essential for eliminating cells in excess or that are no longer necessary to the organism, acting on tissue homeostasis, although the phenomenon is also involved in pathological conditions. Apoptosis promotes activation of biochemical pathways inside cells called caspase pathway, of the proteins responsible for the cleavage of several cell substrates, leading to cell death. Antiapoptotic members of the Bcl-2 family (B cell CLL/lymphoma 2), that belong to the intrinsic route of the activation of caspases, such as Bcl-xL (extra-large B-cell lymphoma) and Bcl-w (Bcl-2-like 2), act predominantly to prevent that pro-apoptotic members, such as Bax (Bcl-2-associated X protein) and Bak (Bcl-2 relative bak) lead to cell death. Antiapoptotic molecules are considered potentially oncogenic. Murine models are known to be valuable systems for the experimental analysis of oncogenes in vivo, and for the identification of pharmacological targets for cancer and to assess antitumor therapies. Given the importance of tumorigenesis studies on the immune responses to cancer and the possibility of investigating the participation of antiapoptotic molecules in tumor progression in vivo, the development of new models may be platforms for studies on tumorigenesis, immune antitumor responses, investigation of the ectopic expression of antiapoptotic molecules and immunotherapies for tumors.

CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma

2011 ◽  
Vol 3 (74) ◽  
pp. 74ra22-74ra22 ◽  
Author(s):  
B. Burington ◽  
P. Yue ◽  
X. Shi ◽  
R. Advani ◽  
J. T. Lau ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Pathway Activation ◽  
Large B Cell ◽  
Activation Status

scholarly journals Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis

2012 ◽  
Vol 209 (2) ◽  
pp. 291-305 ◽  
Author(s):  
Likun Du ◽  
Roujun Peng ◽  
Andrea Björkman ◽  
Noel Filipe de Miranda ◽  
Cornelia Rosner ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Class Switch Recombination ◽  
B Cell Lymphoma ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
End Joining ◽  
Class Switch

Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.

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