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Theses

Super enhancers du locus IgH et lymphomagenèse

Abstract : Numerous mature B cell lymphomas are characterized by oncogenic translocation to the immunoglobulin heavy chain locus (IgH). Most of these translocations occur during the different IgH gene rearrangements punctuating the B cell life. The translocated oncogene appears deregulated by the two main IgH locus transcriptional activators: Eµ and 3'RR. It has been previously shown that the 3'RR is the major player regulating class switch recombination (CSR), through AID recruitment and the induction of DNA double strand breaks (DSBs).During my thesis, the analysis of lymphomas developed by three mouse models bearing c-myc insertion at different positions of the IgH locus showed a transcriptional cooperation of Eµ and 3'RR to promote B cell lymphomagenesis although 3'RR alone is sufficient to induce the development of mature B cell lymphomas. We also showed that 3'RR absence disrupted the proper recruitment of repair factors when resolving CSR breakouts suggesting that 3'RR failure could represent a risk of oncogenic translocation to the IgH locus.The study of the 3'RR mechanism of action showed a difference between normal B cells in which HDAC1 is recruited by the hs1.2 3'RR central element and murin B cell lymphomas where it is the HAT CBP which was recruited by the hs3a and hs3b 3'RR elements. The use of the HDACi SAHA significantly impacted normal B cell proliferation, CSR and Ig synthesis. Only an inconsistent effect was observed during in-vitro murin B cell lymphoma growth.Finally, generation of homozygous kI CmycC mice lead to the development of an interesting model of mature CD138+ B cell lymphomas that can be used for investigations of therapeutics strategies against human myelomas.
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Submitted on : Monday, February 7, 2022 - 6:49:27 PM
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Melissa Ferrad. Super enhancers du locus IgH et lymphomagenèse. Médecine humaine et pathologie. Université de Limoges, 2021. Français. ⟨NNT : 2021LIMO0071⟩. ⟨tel-03560883⟩

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