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.
Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice
Disclosures: R. Beyaert reported grants from Galapagos nv outside the submitted work; in addition, R. Beyaert had a patent to WO09065897 issued. No other disclosures were reported.
- Award Id(s): FWO-1244321N
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Tim Pieters, Sara T’Sas, Stijn Vanhee, André Almeida, Yasmine Driege, Juliette Roels, Wouter Van Loocke, Willem Daneels, Mathijs Baens, Arnaud Marchand, Maaike Van Trimpont, Filip Matthijssens, Julie Morscio, Kelly Lemeire, Béatrice Lintermans, Lindy Reunes, Patrick Chaltin, Fritz Offner, Jo Van Dorpe, Tino Hochepied, Geert Berx, Rudi Beyaert, Jens Staal, Pieter Van Vlierberghe, Steven Goossens; Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice. J Exp Med 4 October 2021; 218 (10): e20202280. doi: https://doi.org/10.1084/jem.20202280
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