Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

• DOI: 10.1172/jci72415
• Publication Date: 2014-11-09T23:00:06Z
• Authors: Stéphanie Sungalee; Emilie Mamessier; Ester Morgado; Emilie Grégoire; Philip Z. Brohawn; Christopher A. Mo...; Nathalie Jouve; Céline Monvoisin; Cédric Menard; Guilhaume Debroas; Mustapha Faroudi; Violaine Mechin; Jean-Marc Navarro; Charlotte Drevet; Franziska C. Eberle; Lionel Chasson; Fannie Baudimont; Stéphane J. Mancini; Julie Tellier; Jean-Michel Picqu...; Rachel Kelly; Paolo Vineis; Philippe Ruminy; Bruno Chetaille; Elaine S. Jaffe; Claudine Schiff; Jean Hardwigsen; David A. Tice; Brandon W. Higgs; Karin Tarte; Bertrand Nadel; Sandrine Roulland
• Keywords: Male; 0301 basic medicine; [SDV]Life Sciences [q-bio]; B-Lymphocyte Subsets; 610; 600; [SDV.CAN]Life Sciences [q-bio]/Cancer; Mice, Transgenic; [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy; Neoplasms, Experimental; [SDV] Life Sciences [q-bio]; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; [SDV.CAN] Life Sciences [q-bio]/Cancer; Proto-Oncogene Proteins c-bcl-2; Cell Movement; Cytidine Deaminase; Animals; Humans; Female; [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy; Lymphoma, Follicular

It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.