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Reproducing the complex development of human Follicular Lymphoma in mouse models

Abstract : Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells. The genetic hallmark that leads to the development of FL is the t(14:18) which occurs early in the bone marrow during B cell development, thereby placing the anti-apoptotic Bcl2 gene under the direct control of the transcriptional enhancers which stand in 3’ of the immunoglobulin heavy chain locus (IgH 3’RR) and leading to the constitutive expression of the BCL2 protein. To assess the impact of the Bcl2 deregulation on B-cell fate and try to reproduce FL development in mice, two models were designed: the Ig-BCL2 (Knock in of the Bcl2 in the immunoglobulin light chain kappa locus) and the 3’RR-BCL2 (Transgene containing Bcl2 and a micro-3’RR), both containing the full BCL2 promoter region. Despite striking differences between both models, we showed that the 3’RR-BCL2 mouse model is the more pertinent for the study of FL . This model indeed leads to a much more GC-focused expression, and ,accordingly, to more significant GC B cell expansion rather than plasma cell expansion. By contrary, pan-B expression of BCL2 in the Igk-BCL2 models culminates with a strong overexpression in plasmablasts and plasma cells. However and whatever the BCL2 configuration, in the absence of additional oncogenic hit, both of our models remained free of GC B cell tumors on the long run and rather ended developing plasmacyttic lymphomas. Thus, to introduce secondary genetic alterations, we crossed our 3’RR-BCL2 mice with other models bringing anomalies known to occur in human FL (BCR N-glycosylation of the V domains, HVEM or KMT2D loss of function). We were able to show that with the addition of these secondary mutations, notably HVEM/KMT2D deletions, our mice developed GC hyperplasia and were eventually able to develop tumors of GC B cell phenotype. This part of our work is still preliminary and more work needs to be done but, all in all, our current study presents strong tools that can be used for further building pertinent FL models and better understanding the complex development of FL.
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Submitted on : Monday, February 7, 2022 - 6:21:08 PM
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Lina Zawil. Reproducing the complex development of human Follicular Lymphoma in mouse models. Human health and pathology. Université de Limoges, 2021. English. ⟨NNT : 2021LIMO0069⟩. ⟨tel-03560858⟩

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