Exploring Epigenetic Dysregulations: The Role of Histone Deacetylases in Multiple Myeloma Pathogenesis

Diplôme Thèse Exploring Epigenetic Dysregulations: The Role of Histone Deacetylases in Multiple Myeloma Pathogenesis eng 2024 2024 author Rincon Rafael 931393 Section des sciences pharmaceutiques (FARMA) director Cuendet Muriel 0000-0002-1523-1907 686755 Section des sciences pharmaceutiques (FARMA) 150 10.13097/archive-ouverte/unige:181261 urn:nbn:ch:unige-1812614 Sc. Vie - Pharma. 310 <p>Multiple myeloma is a hematological malignancy consisting of abnormal plasma cells that uncontrollably proliferate in the bone marrow leading to end-organ damage. It accounts for approximately 19% of newly diagnosed blood malignancies and it is the second most prevalent hematological cancer after non-Hodgkin lymphoma. Despite the expansion of available drugs, current therapies still bring important side effects and practically all patients undergo relapse and refractory events. Therefore, there is a need to improve and refine the therapeutic options. Histone deacetylases were proposed as possible therapeutic targets, but the non-selective inhibition of this group of proteins led to serious adverse events. Histone deacetylase 6 contains a C-terminal zinc-finger ubiquitin-binding protein domain able to recognize ubiquitinated proteins and activate the aggresome pathway. Therefore, it has been proposed as a potential target responsible for resistance to conventional proteasome inhibition therapy. A two-residue mutation inactivating this zinc-finger domain disrupted its interaction with ubiquitin in a cell-free assay. Moreover, a RPMI 8226 multiple myeloma cell line containing this mutation showed a decreased aggresome formation, cell growth and a dysregulated gene expression profile. Genes affected upon this mutation were mainly related to immunological and cell adhesion functions. These results led to the design of small molecules predicted to inhibit the zinc-finger ubiquitin-binding domain, but they did not exert any antiproliferative activity in multiple myeloma cells alone or in combination with proteasome inhibitors. The work presented in this thesis focuses on histone deacetylase 6 as a potential target against multiple myeloma and exposes other proteins that could be relevant in the pathogenesis of the disease.</p> Multiple Myeloma HDAC6 Drug resistance Dewey 615 31 Section des sciences pharmaceutiques 17 false 884 Pharmacognosie c4a35d6c-5b07-41bc-b649-b9cf9da2e21a Thesis Public RINCON_Thesis.pdf 5029995 application/pdf Private 2030-01-01 f43086e2bffff47dc7abd71082a9a412b11ee378afefa9f70e5926a9cddf3d0f 367a4ea5-a248-4d6e-aef1-e609cd629f14 Imprimatur Public Imprimatur_RAFAEL_RINCON.pdf 57643 application/pdf 04a693f1887d33067f069aa62b0ca1ad35fac1120ffaf68a0b7b9299d920cd0c embargoedAccess Faculté des sciences / Section des sciences pharmaceutiques

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Rincon, Rafael

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