Distinct B-Cell Specific Transcriptional Contexts of the BCL2 Oncogene Impact Pre-Malignant Development in Mouse Models

Lina Zawil (1) , Tiffany Marchiol (1) , Baptiste Brauge (2) , Alexis Saintamand (1) , Claire Carrion (1) , Elise Dessauge (2) , Christelle Oblet (1) , Sandrine Le Noir (1) , Frédéric Mourcin (2) , Mylène Brousse (1) , Paco Derouault (3) , Mehdi Alizadeh (2) , Yolla El Makhour (4) , Céline Monvoisin (2) , Julien Saint-Vanne (2, 5) , Simon Leonard (2, 6) , Stéphanie Durand-Panteix (1) , Karin Tarte (2, 5) , Michel Cogné (1, 2, 5)

1 CRIBL - Contrôle de la Réponse Immune B et des Lymphoproliférations
2 MOBIDIC - Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer
3 Hôpital Dupuytren [CHU Limoges]
4 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
5 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
6 LabEX IGO Immunothérapie Grand Ouest

Upregulated expression of the anti-apoptotic oncogene is a common feature of various types of B-cell malignancies, from lymphoma to leukemia or myeloma. It is currently unclear how the various patterns of deregulation observed in pathology eventually impact the phenotype of malignant B cells and their microenvironment. Follicular lymphoma (FL) is the most common non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells, and its major hallmark is the t(14:18) translocation occurring in B cell progenitors and placing the gene under the control of the immunoglobulin heavy chain locus regulatory region (IgH 3'RR), thus exposing it to constitutive expression and hypermutation. Translocation of onto Ig light chain genes, gene amplification, and other mechanisms yielding over-expression are, in contrast, rare in FL and rather promote other types of B-cell lymphoma, leukemia, or multiple myeloma. In order to assess the impact of distinct BCL2 deregulation patterns on B-cell fate, two mouse models were designed that associated and its full P1-P2 promoter region to either the IgH 3'RR, within a "3'RR-" transgene mimicking the situation seen in FL, or an Ig light chain locus context, through knock-in insertion at the Igκ locus ("Igκ-" model). While linkage to the IgH 3' RR mostly yielded expression in GC B-cells, the Igκ-driven up-regulation culminated in plasmablasts and plasma cells, boosting the plasma cell in-flow and the accumulation of long-lived plasma cells. These data demonstrate that the timing and level of BCL2 deregulation are crucial for the behavior of B cells inside GC, an observation that could strongly impact the lymphomagenesis process triggered by secondary genetic hits.

Mots clés: oncogene deregulation; translocation; lymphoma; plasmacytosis; germinal center

Domaines: Sciences du Vivant [q-bio]

Lina Zawil, Tiffany Marchiol, Baptiste Brauge, Alexis Saintamand, Claire Carrion, et al.. Distinct B-Cell Specific Transcriptional Contexts of the BCL2 Oncogene Impact Pre-Malignant Development in Mouse Models. Cancers, 2022, 14 (21), pp.5337. ⟨10.3390/cancers14215337⟩. ⟨hal-03888678⟩