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Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression
Stéphanie Sungalee, … , Bertrand Nadel, Sandrine Roulland
Stéphanie Sungalee, … , Bertrand Nadel, Sandrine Roulland
Published November 10, 2014
Citation Information: J Clin Invest. 2014;124(12):5337-5351. https://doi.org/10.1172/JCI72415.
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Research Article

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

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Abstract

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.

Authors

Stéphanie Sungalee, Emilie Mamessier, Ester Morgado, Emilie Grégoire, Philip Z. Brohawn, Christopher A. Morehouse, 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 Picquenot, 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

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Figure 4

Somatic mutation analysis of BCL2-enriched GC and post-GC subsets by exome sequencing.

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Somatic mutation analysis of BCL2-enriched GC and post-GC subsets by exo...
(A) Histograms of the mean number (± SEM) of nonsilent SNVs in BCL2-enriched GC and post-GC subsets from BCL2 and control mice. (B) Frequency distribution of VAFs for all the gene loci variants identified in each B cell subset from BCL2-transduced versus control (empty vector) mice. (C) Base-level transitions and transversions of all variant loci shown in B.
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