2. Academic Validation
  3. Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice

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

  • J Exp Med. 2021 Oct 4;218(10):e20202280. doi: 10.1084/jem.20202280.
Tim Pieters 1 2 3,  Sara T'Sas 1 2 3,  Stijn Vanhee 4 5,  André Almeida 1 2 3,  Yasmine Driege 4 6,  Juliette Roels 1 2 3,  Wouter Van Loocke 1 2 3,  Willem Daneels 3 5 7,  Mathijs Baens 8,  Arnaud Marchand 8,  Maaike Van Trimpont 1 2 3,  Filip Matthijssens 1 2 3,  Julie Morscio 1 2 3,  Kelly Lemeire 4 6,  Béatrice Lintermans 1 2 3,  Lindy Reunes 1 2 3,  Patrick Chaltin 8 9,  Fritz Offner 3 7,  Jo Van Dorpe 10 11,  Tino Hochepied 4 6,  Geert Berx 3 4 6,  Rudi Beyaert 4 6,  Jens Staal 4 6,  Pieter Van Vlierberghe  # 1 2 3,  Steven Goossens  # 1 2 3 10
Affiliations

Affiliations

  • 1 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • 2 Center for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.
  • 3 Cancer Research Institute Ghent, Ghent, Belgium.
  • 4 Center for Inflammation Research, Flemish Institute for Biotechnology, Ghent, Belgium.
  • 5 Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
  • 6 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 7 Department of Hematology, Ghent University Hospital, Ghent, Belgium.
  • 8 Center for Innovation and Stimulation of Drug Discovery Leuven, Leuven, Belgium.
  • 9 Center for Drug Design and Discovery, Catholic University of Leuven, Leuven, Belgium.
  • 10 Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
  • 11 Department of Pathology, Ghent University Hospital, Ghent, Belgium.
  • # Contributed equally.
PMID: 34406363 DOI: 10.1084/jem.20202280
Abstract

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.

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