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

Stéphanie Sungalee (1) , Emilie Mamessier (1) , Ester Morgado (1) , Emilie Grégoire (2) , Philip Brohawn (3) , Christopher Morehouse (3) , Nathalie Jouve (1) , Céline Monvoisin (4, 5) , Cédric Menard (4, 5) , Guilhaume Debroas (1) , Mustapha Faroudi (1) , Violaine Mechin (1) , Jean-Marc Navarro (1) , Charlotte Drevet (1) , Franziska Eberle (6) , Lionel Chasson (1) , Fannie Baudimont (1) , Stéphane Mancini (1) , Julie Tellier (1) , Jean-Michel Picquenot (7, 8) , Rachel Kelly (9) , Paolo Vineis (9) , Philippe Ruminy (7, 8) , Bruno Chetaille (10) , Elaine Jaffe (6) , Claudine Schiff (1) , Jean Hardwigsen (2) , David Tice (3) , Brandon Higgs (3) , Karin Tarte (4, 5) , Bertrand Nadel (1) , Sandrine Roulland (1)

1 CIML - Centre d'Immunologie de Marseille - Luminy
2 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
3 MedImmune
4 MiCa - Microenvironnement et cancer
5 EFS Bretagne - Etablissement français du sang [Rennes]
6 NCI-NIH - National Cancer Institute [Bethesda]
7 GPL - Groupe d'étude des proliférations lymphoïdes
8 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
9 Imperial College London
10 Institut Paoli-Calmettes

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.

Domains: Life Sciences [q-bio]; Immunology; Immunotherapy; Life Sciences [q-bio]; Cancer

Stéphanie Sungalee, Emilie Mamessier, Ester Morgado, Emilie Grégoire, Philip Brohawn, et al.. Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression. Journal of Clinical Investigation, 2014, 124 (12), pp.5337-5351. ⟨10.1172/JCI72415⟩. ⟨hal-03606419⟩