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 8

Clonal divergence between FLLCs and memory B cells in blood and tissues.

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Clonal divergence between FLLCs and memory B cells in blood and tissues....
(A) Schematic representation of ICV accumulating during clonal expansion in the presence of AID. Distinct subclones are designated with distinct colors. (B) Genealogical trees generated from t(14;18)+ subclones issued from 4 organ donors and 1 FLIS. Trees are rooted from an identical BCL2/JH breakpoint and organized based on ICV in the Sμ/Sγ regions of the translocated allele. Shared mutations were used to define putative intermediate filiation (white circles). Stepwise accumulation of mutations is indicated by the numbers above the branches (+1 to +64). Total mutations are summarized at the end of each branch. Dashed arrows indicate ongoing CSR. ISD, intra-switch deletion. (C) Genealogical trees generated from memory B cells issued from 5 organ donors. Trees are rooted from an identical VH (D)JH junction and organized based on ICV in the VH region. Identical subclones (no ICV) are boxed. (D) SHM rate in the switch regions from t(14;18)+ B cells, IgM+CD27+ B cells, and switched memory B cells. The rate is given as a percentage per 1,000 bp. (E) Aberrant CSR in t(14;18)+ variants from a paired BM/blood sample (TS #9). The amplified PCR fragments were cloned and sequenced. Arrows indicate the positions of ongoing CSR breaks and are represented below. Some clones displayed an inversion of part of the Sμ region. OD, organ donor; TS, thoracic surgery.