HDAC6 inhibition decreases leukemic stem cell expansion driven by Hedgehog hyperactivation by restoring primary ciliogenesis.

Autor: Pezzotta A; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy., Gentile I; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy., Genovese D; Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia IRCCS, Milano, Italy., Totaro MG; IFOM (FIRC Institute of Molecular Oncology, Milano, Italy., Battaglia C; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy., Leung AY; Department of Medicine, LSK Faculty of Medicine, Hong Kong, China., Fumagalli M; Hospital San Gerardo, Clinica Ematologica e Centro Trapianti di Midollo Osseo, Monza, Italy., Parma M; Hospital San Gerardo, Clinica Ematologica e Centro Trapianti di Midollo Osseo, Monza, Italy., Cazzaniga G; Centro Ricerca Tettamanti, Clinica Pediatrica Università di Milano-Bicocca, Centro Maria Letizia Verga, Monza, Italy., Fazio G; Centro Ricerca Tettamanti, Clinica Pediatrica Università di Milano-Bicocca, Centro Maria Letizia Verga, Monza, Italy., Alcalay M; Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia IRCCS, Milano, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milano, Italy., Marozzi A; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy., Pistocchi A; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy. Electronic address: anna.pistocchi@unimi.it.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2022 Sep; Vol. 183, pp. 106378. Date of Electronic Publication: 2022 Jul 30.
DOI: 10.1016/j.phrs.2022.106378
Abstrakt: Aberrant activation of the Hh pathway promotes cell proliferation and multi-drug resistance (MDR) in several cancers, including Acute Myeloid Leukemia (AML). Notably, only one Hh inhibitor, glasdegib, has been approved for AML treatment, and most patients eventually relapse, highlighting the urgent need to discover new therapeutic targets. Hh signal is transduced through the membrane of the primary cilium, a structure expressed by non-proliferating mammalian cells, whose stabilization depends on the activity of HDAC6. Here we describe a positive correlation between Hh, HDAC6, and MDR genes in a cohort of adult AML patients, human leukemic cell lines, and a zebrafish model of Hh overexpression. The hyper-activation of Hh or HDAC6 in zebrafish drove the increased proliferation of hematopoietic stem and progenitor cells (HSPCs). Interestingly, this phenotype was rescued by inhibition of HDAC6 but not of Hh. Also, in human leukemic cell lines, a reduction in vitality was obtained through HDAC6, but not Hh inhibition. Our data showed the presence of a cross-talk between Hh and HDAC6 mediated by stabilization of the primary cilium, which we detect for the first time in zebrafish HSPCs. Inhibition of HDAC6 activity alone or in combination therapy with the chemotherapeutic agent cytarabine, efficiently rescued the hematopoietic phenotype. Our results open the possibility to introduce HDAC6 as therapeutic target to reduce proliferation of leukemic blasts in AML patients.
Competing Interests: Conflict of interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Conflict of interest statement All authors declare that they have no conflict of interest. Declaration of interest: none.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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