scholarly journals Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma

10.3791/56023 ◽  
2018 ◽  
Author(s):  
Archana Vijaya Kumar ◽  
Carmen Donate ◽  
Beat A. Imhof ◽  
Thomas Matthes
Keyword(s):  
Mouse Model ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Xenograft Mouse Model ◽  
Mantle Cell

Combination Of Ibrutinib With ABT-199, a BCL-2 Pathway Inhibitor: Effective Therapeutic Strategy In a Novel Mantle Cell Lymphoma Cell Line Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 645-645 ◽  
Author(s):  
Xiaoxian Zhao ◽  
Juraj Bodo ◽  
Danyu Sun ◽  
Jeffrey J. Lin ◽  
Lisa Durkin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Therapeutic Strategy ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Down Regulation ◽  
Mantle Cell ◽  
Bcr Signaling ◽  
Nsg Mouse

Abstract Background Mantle cell lymphoma (MCL) is an aggressive subtype of Non-Hodgkin Lymphoma associated with poor prognosis. Constitutive activation of B-cell receptor (BCR) signaling plays an essential role for the survival and proliferation of malignant B-cells. Targeting Bruton’s tyrosine kinase (BTK), a component of BCR signaling pathway, with ibrutinib is a promising strategy. As a single agent, complete and partial response rates of 21% and 47%, respectively, were observed in a phase 2 study for relapsed or refractory MCL. Simultaneous inhibition of multiple biologic pathways has the potential to result in a synergism. We combined ibrutinib with ABT-199, a BH3 mimetic that selectively targets the BCL-2 pathway, and tested their in vitroefficacy against MCL. Experimental design A novel MCL cell line, CCMCL1, and four other MCL cell lines (Jeko-1, Mino, JVM2, Rec-1) were used for flow cytometry-based apoptosis and cell cycle analyses to evaluate the combinational effect of ibrutinib with ABT-199 (ChemieTek. Indianpolis. IN). The interaction between drugs was examined with Calcusyn software and combination index values served to determine the combined effect as synergistic (<1), additive (=1), or antagonistic (>1). Immunoblotting was performed to investigate signaling pathways of MCL cells exposed to these agents. Results CCMCL1 was derived from primary leukemic MCL cells. Cells were initially directly injected via tail vein into an NSG mouse. Engrafted cells were then isolated at 10 weeks from spleen and placed into routine cell culture. Immunophenotyping showed CCMCL1 cells have similar characteristics as the primary patient MCL cells, which expressed CD5, CD19, CD20, FMC7 and monotypic kappa light chain. Immunohistochemical staining of engrafted mouse spleen tissue showed expression of cyclin D1 and SOX11. The karyotype is highly complex with an IGH@/CCND1 fusion by metaphase FISH. In addition to spleen, MCL cell infiltration was observed in mouse liver, bone marrow, blood, brain, lung, kidney and intestine. In vitro cultured CCMCL1 cells underwent apoptosis upon expose to ibrutinib and ABT-199 as single agents. Combination of these two drugs resulted in synergistic induction of apoptosis (Table 1). Synergism was also observed with Jeko-1, Mino, JVM-2 and Rec-1 cells. Immunoblotting showed CCMCL1 cells have constitutive expression of cyclin D1, SOX11, PAX5 and MCL1. Ibrutinib as a single agent induced a rapid down-regulation of SOX11 and MCL1, while combination of ibrutinib with ABT-199 further enhanced down regulation of SOX11, followed by down-regulation of PAX5 at a later time point. We are currently testing the in vivo efficacy of combining these two drugs in a CCMCL1 NSG mouse model. Conclusion Our CCMCL1/NSG mouse model is a new model for pre-clinical assessment of MCL treatment approaches. Combination of ibrutinib with ABT-199 has synergistic effect of apoptotic induction in CCMCL1 as well as four other MCL cell lines tested. Ibrutinib or ibruitnib/ABT-199 combination induced apoptosis of MCL is associated with down-regulation of SOX11 and PAX5. Simultaneous down regulation of MCL1 via ibrutinib and targeting of BCL2 may contribute to the in vitrosynergism observed. These data support further investigation of this novel therapeutic strategy. Disclosures: No relevant conflicts of interest to declare.

Cyclin D2 Overexpression Recapitulates Mantle Cell Lymphoma in Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1748-1748
Author(s):  
Tim Pieters ◽  
Steven Goossens ◽  
Sara T'Sas ◽  
Geert Berx ◽  
Jody J. Haigh ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Luciferase Reporter ◽  
Cyclin D2 ◽  
Genetic Event ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is a highly aggressive subtype of B-cell lymphoma that is characterized by a poor response to current treatment regimens. Most MCLs carry a prototypical translocation, t(11;14), which juxtaposes the CCND1 gene towards the immunoglobulin heavy chain (IGH) locus, resulting in cyclin D1 overexpression. Strikingly, MCL has not been recapitulated in transgenic mouse models of Ccnd1 overexpression alone. Notably, a subset of MCL patients are cyclin D1 negative but instead overexpress cyclin D2 (encoded by CCND2)as a consequence of recurrent genomic rearrangements involving the CCND2 locus. Here, we developed a novel conditional ROSA26-driven Ccnd2 overexpression mouse model and showed that hematopoietic-specific Ccnd2 activation is sufficient to drive MCL formation in mice. Starting from 36 weeks, these mice develop huge B-cell lymphomas and these tumor cells have the typical MCL morphology, are Sox11 positive and disseminate into other organs, all typical features of MCL. In addition, preliminary shallow sequencing analysis revealed a somatic Crlf2 deletion as a cooperative genetic event in one of the murine Ccnd2-driven MCL tumors. In this study, we want to further validate and characterize this novel Ccnd2-driven mouse model for MCL and test putative synergisms between Ccnd2 overexpression and other recurrent cooperating genetic lesions that occur in human MCL, such as loss of p53 or SOX11 activation. Noteworthy, the MCL cells from this mouse model also contain a luciferase reporter, allowing accurate in vivo tracing of tumor cells in xenograft experiments. These xenograft experiments can be used as preclinical models, in which bioluminescence is used to asses the tumor burden and to monitor tumor regression upon drug treatment. In conclusion, we have developed a novel mouse model in which Ccnd2 overexpression faithfully recapitulates MCL and this model will allow us to understand the molecular mechanisms that drive MCL and identify and test novel drugs to treat this aggressive and until now incurable disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals A mouse model of disseminated mantle cell lymphoma highlights a lack of activity of estrogen receptor β agonists toward tumor burden

2017 ◽  
Vol 59 (7) ◽  
pp. 1726-1729
Author(s):  
Simon Body ◽  
Anna Esteve-Arenys ◽  
Clara Recasens-Zorzo ◽  
Xavier Troussard ◽  
Gaël Roué ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mouse Model ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Estrogen Receptor Β ◽  
Mantle Cell

scholarly journals Takes one to B1a: Dismantling the origin of mantle cell lymphoma

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Anna E. Beaudin
Keyword(s):  
Mouse Model ◽  
Mantle Cell Lymphoma ◽  
Mouse Models ◽  
Human Disease ◽  
Cell Lymphoma ◽  
Cell Of Origin ◽  
Cyclin D2 ◽  
B1a Cells ◽  
Mantle Cell

Therapeutic discovery for mantle cell lymphoma (MCL) has been hindered by a lack of preclinical mouse models that recapitulate human disease. In this issue, Pieters and colleagues (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202280) establish a novel mouse model of MCL driven by overexpression of cyclin D2 and identify fetal-derived B1a cells as putative cell of origin for MCL.

scholarly journals Combined Administration of Rituximab and ON 013105 Induces Apoptosis in Mantle Cell Lymphoma Cells and Reduces Tumor Burden in a Mouse Model of Mantle Cell Lymphoma

2012 ◽  
Vol 19 (1) ◽  
pp. 85-95 ◽  
Author(s):  
Anil Prasad ◽  
Ashutosh Shrivastava ◽  
Evangelos Papadopoulos ◽  
Paula M. Kuzontkoski ◽  
M.V. Ramana Reddy ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Lymphoma Cells ◽  
Mantle Cell ◽  
Combined Administration

scholarly journals A Severe Combined Immunodeficient–hu In vivo Mouse Model of Human Primary Mantle Cell Lymphoma

2008 ◽  
Vol 14 (7) ◽  
pp. 2154-2160 ◽  
Author(s):  
Michael Wang ◽  
Liang Zhang ◽  
Xiaohong Han ◽  
Jing Yang ◽  
Jianfei Qian ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell

Mantle Cell Lymphoma Rising in Association with Inverted Papilloma

2019 ◽  
Author(s):  
Charles Tong ◽  
Peter Papagiannopoulos ◽  
Michael Feldman ◽  
Nithin Adappa ◽  
James Palmer
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Inverted Papilloma ◽  
Mantle Cell

Mantle Cell Lymphoma Presenting with Unusual Morphology in an Adolescent Female: A Case Report and Review of the Literature

2006 ◽  
Vol preprint (2007) ◽  
pp. 1
Author(s):  
Kristi Smock ◽  
Hassan Yaish ◽  
Mitchell Cairo ◽  
Mark Lones ◽  
Carlynn Willmore-Payne ◽  
...  
Keyword(s):  
Case Report ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Adolescent Female ◽  
Review Of The Literature ◽  
Mantle Cell
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