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

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 2

Chronic immunization drives preferential accumulation and reentry of activated BCL2+ B cells in the GC.

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Chronic immunization drives preferential accumulation and reentry of act...
(A) Schematic of BMT and chronic immunization assays; hematopoietic stem cells were transduced with an inactive (unrearranged) huBCL2, a small fraction of which (~10–5) will rearrange (and thus express huBCL2) during pro–B cell differentiation. (B) Distribution of the splenic B cell subsets by flow cytometric analysis from unchallenged versus chronically immunized huBCL2-transduced and control animals. Spleens were collected after 6 and 9 months, respectively. Values are shown as the means ± SEM from 3 independent experiments with 2 to 4 mice per group. *P < 0.05 and **P < 0.01 by Student’s t test. (C) Representative flow cytometric profiles of splenocytes and peripheral LNs (inguinal, brachial, and mesenteric) from control (empty vector) and huBCL2-transduced mice with or without chronic immunization. (D) Relative proportion of huBCL2+ cells in the indicated splenic B cell subsets from unchallenged versus chronically immunized huBCL2 -transduced animals. Note that in the absence of immunization, the percentage of EYPF+ cells was less than 1%. (E and F) Frequency of huBCL2+ cells identified by FACS as in C are plotted for the whole cohort of chronically immunized mice. Spleen (left panel) and LNs (right panel). Values from individual mice are shown, summarizing 3 retroviral transduction experiments, with 2 to 4 mice per group, except for WT and Aid-Cre Rosa-EYFP mice (1 mouse/experiment). (G) FACS analysis showing surface IgM expression in BCL2+ GC and post-GC B cells from BCL2-transduced mice.