Eléments cis-régulateurs du locus IgH et lymphomagenèse B

Abstract : The immunoglobulin heavy chain locus (IgH) undergoes several changes along B-cell differentiation. VHDJH recombinations during the early stages give the diversity of the antigenic repertoire. Somatic hypermutation (SHM) and class switch recombination (CSR) during late stages allow affinity maturation and the acquisition of new effectors functions. These rearrangements are highly regulated and are under the control of the IgH locus cis-regulatory elements. The 5’ Eµ enhancer is important for VHDJH recombination. The 3’ regulatory region (3’ RR) is essential for both CSR and SHM. These events induce breaks into the IgH locus, making it a hotspot for oncogenic translocations. The aim of my thesis was to understand the transcriptional interactions between Eμ and 3'RR enhancers and to evaluate whether the targeting of the latter could be of a potential therapeutic approach. We have demonstrated that 3'RR is essential to control IgH transcription in mature B cells. It is dispensable during the initial stages of developement (VHDJH recombinations). At the pro-B cell stage, it has a silencer effect rather than a transcriptional one on the DJH segments expression. The analysis of lymphomagenesis in three mice models carrying an insertion of Myc in different locations at the IgH locus showed significant differences in lymphoma kinetics, phenotypes and proliferation index. 3'RR alone, as a major transcriptional activator of the IgH locus, is capable of leading to B-cell lymphomas. Its absence is not detrimental for the development of classical inflammatory/immune reactions. Its targeting may be of a potentially interesting therapeutic approach to decrease its transcriptional activity on the translocated oncogene. A potential role for histone deacetylase inhibitors is under study.
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Nour Ghazzaui. Eléments cis-régulateurs du locus IgH et lymphomagenèse B. Médecine humaine et pathologie. Université de Limoges, 2018. Français. ⟨NNT : 2018LIMO0058⟩. ⟨tel-01988409⟩

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