The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.Leukemia advance online publication, 30 June 2017; doi:10.1038/leu.2017.183.

SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis

Martinelli, G;Mancini, M;De Benedittis, C;Rondoni, M;Papayannidis, C;Manfrini, M;Guadagnuolo, V;Fontana, M. C;Bavaro, L;Padella, A;Tosi, P;Cavo, M;Soverini, S.
2018

Abstract

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.Leukemia advance online publication, 30 June 2017; doi:10.1038/leu.2017.183.
2018
Martinelli, G; Mancini, M; De Benedittis, C; Rondoni, M; Papayannidis, C; Manfrini, M; Meggendorfer, M; Calogero, R; Guadagnuolo, V; Fontana, M. C; Bavaro, L; Padella, A; Zago, E; Pagano, L; Zanotti, R; Scaffidi, L; Specchia, G; Albano, F; Merante, S; Elena, C; Savini, P; Gangemi, D; Tosi, P; Ciceri, F; Poletti, G; Riccioni, L; Morigi, F; Delledonne, M; Haferlach, T; Cavo, M; Valent, P; Soverini, S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/614584
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