SETD2 loss of function as a new marker of advanced disease in systemic mastocytosis: biological and clinical implications

Rondoni, Michela (2020) SETD2 loss of function as a new marker of advanced disease in systemic mastocytosis: biological and clinical implications, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Oncologia, ematologia e patologia, 32 Ciclo. DOI 10.6092/unibo/amsdottorato/9375.
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This project stems from the results of a WES analysis of a rare case of KIT mutation-negative mast cell leukemia (MCL), that identified biallelic inactivating mutations of the SETD2 gene. SETD2 is a tumor suppressor whose loss of function is implicated in solid tumors and leukemias. We thus moved to investigate the prevalence, the underlying mechanisms, the pathogenetic role and the ‘druggability’ of SETD2 loss of function in SM, and its clinical relevance. Screening of a validation cohort of 57 patients with various forms of SM for H3K36 trimethylation levels as a surrogate marker for SETD2 loss of function by WB showed reduced or absent levels in all cases with AdvSM, and significantly lower median SETD2 and H3K36 trimethylation levels resulted in patients with advanced SM as compared to patients with indolent SM. Thus, SETD2 impaired/loss of function can be considered a general phenomenon in SM, correlating with the aggressiveness of the disease. Interestingly, we uncovered a novel post-translational mechanism of hyperubiquitination and enhanced degradation of the protein, and that inhibition of proteasome-mediated degradation is able to rescue SETD2 expression and function. We explored the MDM2 ubiquitin role and the p53 checkpoint involvement. We demonstrated that phosphorylation by Aurora kinase A is the main trigger for this mechanism. We then tested proteasome inhibitor, MDM2 and AKA inhibitors in vitro in cell lines and primary patient cells aimed to revert SETD2 non genomic loss of function. We also explored the cellular effect of midostaurin. Finally, we investigated the clinical significance of SETD2 loss of function in a cohort of 88 patients with various forms of SM assessing the prognostic value of SET2 and H3K36 trimethylation levels in the context of other relevant clinical and laboratory variables, and found that reduced SETD2 and H3K36 trimethylation levels significantly correlate with shorter overall survival.

Tipologia del documento
Tesi di dottorato
Rondoni, Michela
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
systemic mastocytosis
Data di discussione
26 Marzo 2020

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