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Etude du rôle de MYD88 et des voies NF-kB dans l'émergence des lymphomes B

Abstract : It was estimated that 557 730 deaths from lymphoma worldwide in 2018 and are the 5th leading cause of cancer death in France. Basic and applied research in this area is therefore crucial to improve diagnostics and therapies. Cell signaling pathways of the transcription factor NF-κB, playing a central role in cell survival and proliferation, are frequently deregulated and involved in the emergence of non-Hodgkin B-cell lymphomas (B-NHL). The laboratory studies over these three years concerned the role of MYD88 and NF-κB in the context of the emergence of B cell-linked lymphomas. The L265P mutation of protein adaptor MYD88 (MYD88L265P), exacerbating toll-like receptor (TLR) signaling, receptors involved in the innate immune B cell response, results in constitutive NF-κB activation. This mutated protein MYD88L265P is found in many cases of LNH ranging from indolent lymphoplasmacytic lymphomas (LPL) to aggressive diffuse large B-cell lymphomas (DLBCL). Waldenström's macroglobulinemia (WM) presents in about 90% of cases this MYD88L265P mutation, making it a primary event in the emergence of this LPL. To study the consequences of this mutation on the transformation of the B cell, we carried out a in vivo study, thanks to a murine model expressing MYD88L252P (murine ortholog of the MYD88L265P mutation in humans) exclusively in B cells through the expression of CRE-recombinase due to the Cd19 promotor. Indeed, the study of this model developing a lymphoma close to WM, allowed us to visualize its transforming power on the B cell, but also the behavior of the cell in the microenvironment of an entire organism. We were able to confirm the ability of MYD88L252P to form a lymphoplasmacytic clone, as well as the presence of a serum monoclonal IgM peak and an IgM plasma cells invasion in the bone marrow, which are characteristics of WM.Immune escape is a major component in the emergence of B-LNH. In the case of lymphomas linked to the Epstein Barr virus (EBV), the B cells immortalized by this virus are also able to modulate the immune response. Regarding this last phenomenon, we have described the immunoregulatory profile in vitro of B cells infected by EBV in latency III. The LMP1 protein, produced during latency II and III, essentially activating the NF-κB alternative pathway, allows the overexpression of the immunomodulatory proteins PD-L1, IL-10, TGF-β1 and IL35 (EBI3 and IL12A). We have also demonstrated the expansion of conventional and unconventional regulatory T cells (Tregs) depending on the PD-1/PD-L1 axis. In many cancers, the PD-L1 surface protein is overexpressed, strongly impacting the microenvironment of tumor cells. Thus, in the case of DLBCL, this overexpression associated to poor prognosis. Due to its importance in the progression of the tumor, therapeutic tests with anti-PD-L1 antibodies can be very effective. For this, we did preclinical in vivo tests targeting PD-L1 directly, and ex vivo targeting the pathways allowing its expression. The L.CD40 (lmp1/cd40) murine model developing indolent lymphoma close to marginal zone lymphoma (MZL), in which we shown the overexpression of PD-L1 from tumoral B cells. We were able to demonstrate the beneficial effects of this treatment with a in vivo spleen size reduction and ex vivo PD-L1 downregulation, as well as T cell reactivation. These studies open new research perspectives on our MYD88 mouse model.
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Submitted on : Wednesday, April 7, 2021 - 12:18:36 PM
Last modification on : Wednesday, October 5, 2022 - 4:01:47 AM


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  • HAL Id : tel-03191615, version 1



Lilian Roland. Etude du rôle de MYD88 et des voies NF-kB dans l'émergence des lymphomes B. Médecine humaine et pathologie. Université de Limoges, 2021. Français. ⟨NNT : 2021LIMO0014⟩. ⟨tel-03191615⟩



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