Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression.
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.
Stéphanie
S
Sungalee
Emilie
E
Mamessier
Ester
E
Morgado
Emilie
E
Grégoire
Philip Z
PZ
Brohawn
Christopher A
CA
Morehouse
Nathalie
N
Jouve
Céline
C
Monvoisin
Cédric
C
Menard
Guilhaume
G
Debroas
Mustapha
M
Faroudi
Violaine
V
Mechin
Jean-Marc
JM
Navarro
Charlotte
C
Drevet
Franziska C
FC
Eberle
Lionel
L
Chasson
Fannie
F
Baudimont
Stéphane J
SJ
Mancini
Julie
J
Tellier
Jean-Michel
JM
Picquenot
Rachel
R
Kelly
Paolo
P
Vineis
Philippe
P
Ruminy
Bruno
B
Chetaille
Elaine S
ES
Jaffe
Claudine
C
Schiff
Jean
J
Hardwigsen
David A
DA
Tice
Brandon W
BW
Higgs
Karin
K
Tarte
Bertrand
B
Nadel
Sandrine
S
Roulland
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase