SETD2 non genomic loss of function in advanced systemic mastocytosis is mediated by an Aurora kinase A/MDM2 axis and can be therapeutically targeted.

Autor: Mancini M; IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Istituto Di Ematologia 'Seràgnoli', Bologna, Italy. mancini_manu@yahoo.com., Monaldi C; Dipartimento Di Medicina Specialistica, Diagnostica E Sperimentale, Università Di Bologna, Bologna, Italy., De Santis S; Dipartimento Di Medicina Specialistica, Diagnostica E Sperimentale, Università Di Bologna, Bologna, Italy., Papayannidis C; IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Istituto Di Ematologia 'Seràgnoli', Bologna, Italy., Rondoni M; AUSL Romagna, Hematology Unit, Ravenna, Italy., Sartor C; IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Istituto Di Ematologia 'Seràgnoli', Bologna, Italy.; Dipartimento Di Medicina Specialistica, Diagnostica E Sperimentale, Università Di Bologna, Bologna, Italy., Bruno S; Dipartimento Di Medicina Specialistica, Diagnostica E Sperimentale, Università Di Bologna, Bologna, Italy., Pagano L; Divisione Di Ematologia Geriatrica Ed Emopatie Rare, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS - Università Cattolica del Sacro Cuore, Roma, Italy., Criscuolo M; Dipartimento Di Diagnostica Per Immagini, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Radioterapia Oncologica Ed Ematologia, Roma, Italy., Zanotti R; Section of Hematology, Multidisciplinary Outpatients Clinics for Mastocytosis, Department of Medicine, University Hospital of Verona, Verona, Italy., Bonifacio M; Section of Hematology, Multidisciplinary Outpatients Clinics for Mastocytosis, Department of Medicine, University Hospital of Verona, Verona, Italy., Tosi P; Hematology Unit, Infermi Hospital, Rimini, Italy., Arock M; Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre Et Marie Curie University (UPMC), Paris, France., Valent P; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute of Hematology and Oncology, Medical University of Vienna, Vienna, Austria., Cavo M; IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Istituto Di Ematologia 'Seràgnoli', Bologna, Italy.; Dipartimento Di Medicina Specialistica, Diagnostica E Sperimentale, Università Di Bologna, Bologna, Italy., Soverini S; Dipartimento Di Medicina Specialistica, Diagnostica E Sperimentale, Università Di Bologna, Bologna, Italy.
Jazyk: angličtina
Zdroj: Biomarker research [Biomark Res] 2023 Mar 10; Vol. 11 (1), pp. 29. Date of Electronic Publication: 2023 Mar 10.
DOI: 10.1186/s40364-023-00468-7
Abstrakt: Background: The SETD2 tumor suppressor gene encodes a histone methyltransferase that safeguards transcription fidelity and genomic integrity via trimethylation of histone H3 lysine 36 (H3K36Me3). SETD2 loss of function has been observed in solid and hematologic malignancies. We have recently reported that most patients with advanced systemic mastocytosis (AdvSM) and some with indolent or smoldering SM display H3K36Me3 deficiency as a result of a reversible loss of SETD2 due to reduced protein stability.
Methods: Experiments were conducted in SETD2-proficient (ROSA KIT D816V ) and -deficient (HMC-1.2) cell lines and in primary cells from patients with various SM subtypes. A short interfering RNA approach was used to silence SETD2 (in ROSA KIT D816V cells), MDM2 and AURKA (in HMC-1.2 cells). Protein expression and post-translational modifications were assessed by WB and immunoblotting. Protein interactions were tested by using co-immunoprecipitation. Apoptotic cell death was evaluated by flow cytometry after annexin V and propidium iodide staining, respectively. Drug cytotoxicity in in vitro experiments was evaluated by clonogenic assays.
Results: Here, we show that the proteasome inhibitors suppress cell growth and induce apoptosis in neoplastic mast cells by promoting SETD2/H3K36Me3 re-expression. Moreover, we found that Aurora kinase A and MDM2 are implicated in SETD2 loss of function in AdvSM. In line with this observation, direct or indirect targeting of Aurora kinase A with alisertib or volasertib induced reduction of clonogenic potential and apoptosis in human mast cell lines and primary neoplastic cells from patients with AdvSM. Efficacy of Aurora A or proteasome inhibitors was comparable to that of the KIT inhibitor avapritinib. Moreover, combination of alisertib (Aurora A inhibitor) or bortezomib (proteasome inhibitor) with avapritinib allowed to use lower doses of each drug to achieve comparable cytotoxic effects.
Conclusions: Our mechanistic insights into SETD2 non-genomic loss of function in AdvSM highlight the potential value of novel therapeutic targets and agents for the treatment of patients who fail or do not tolerate midostaurin or avapritinib.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: