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

TitleHDAC6 inhibition decreases leukemic stem cell expansion driven by Hedgehog hyperactivation by restoring primary ciliogenesis
Authors
Pezzotta, AlexGentile, IlariaGenovese, DonatellaTotaro, Maria GraziaBattaglia, CristinaLeung, Anskar Yu-HungFumagalli, MonicaParma, MatteoCazzaniga, GianniFazio, GraziaAlcalay, MyriamMarozzi, AnnaPistocchi, Anna
KeywordsAML
cyclopamine hydrate C4116 (Sigma)
cytarabine PHR1787 (Sigma)
Dymetil sulfoxide D8418 (Sigma)
Glasdegib PZ0303 (Sigma)
HDAC6
Hedgehog
Primary cilium
Roscovitine R7772 (Sigma)
TubastatinA hydrochloride SML0044 (Sigma)
Zebrafish
Issue Date30-Jul-2022
PublisherElsevier
Citation
Pharmacological Research, 2022, v. 183 How to Cite?
DOI: http://dx.doi.org/10.1016/j.phrs.2022.106378
Abstract

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.


Persistent Identifierhttp://hdl.handle.net/10722/338940
ISSN
1043-6618
2023 Impact Factor: 9.1
2023 SCImago Journal Rankings: 2.160
ISI Accession Number ID
WOS:000844306400004

 

DC FieldValueLanguage
dc.contributor.authorPezzotta, Alex-
dc.contributor.authorGentile, Ilaria-
dc.contributor.authorGenovese, Donatella-
dc.contributor.authorTotaro, Maria Grazia-
dc.contributor.authorBattaglia, Cristina-
dc.contributor.authorLeung, Anskar Yu-Hung-
dc.contributor.authorFumagalli, Monica-
dc.contributor.authorParma, Matteo-
dc.contributor.authorCazzaniga, Gianni-
dc.contributor.authorFazio, Grazia-
dc.contributor.authorAlcalay, Myriam-
dc.contributor.authorMarozzi, Anna-
dc.contributor.authorPistocchi, Anna-
dc.date.accessioned2024-03-11T10:32:41Z-
dc.date.available2024-03-11T10:32:41Z-
dc.date.issued2022-07-30-
dc.identifier.citationPharmacological Research, 2022, v. 183-
dc.identifier.issn1043-6618-
dc.identifier.urihttp://hdl.handle.net/10722/338940-
dc.description.abstract<p>Aberrant activation of the <em>Hh</em> pathway promotes <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cell-proliferation" title="Learn more about cell proliferation from ScienceDirect's AI-generated Topic Pages">cell proliferation</a> and multi-drug resistance (MDR) in several cancers, including <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/acute-myeloid-leukemia" title="Learn more about Acute Myeloid Leukemia from ScienceDirect's AI-generated Topic Pages">Acute Myeloid Leukemia</a> (AML). Notably, only one <em>Hh</em> inhibitor, <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/glasdegib" title="Learn more about glasdegib from ScienceDirect's AI-generated Topic Pages">glasdegib</a>, has been approved for AML treatment, and most patients eventually relapse, highlighting the urgent need to discover new therapeutic targets. <em>Hh</em> 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 <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/histone-deacetylase-6" title="Learn more about HDAC6 from ScienceDirect's AI-generated Topic Pages">HDAC6</a>. Here we describe a positive correlation between <em>Hh</em>, <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/histone-deacetylase-6" title="Learn more about HDAC6 from ScienceDirect's AI-generated Topic Pages">HDAC6</a>, and <em>MDR</em> genes in a cohort of adult AML patients, human leukemic cell lines, and a zebrafish model of <em>Hh</em> overexpression. The hyper-activation of <em>Hh</em> 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 <em>Hh</em>. Also, in human leukemic cell lines, a reduction in vitality was obtained through HDAC6, but not <em>Hh</em> inhibition. Our data showed the presence of a cross-talk between <em>Hh</em> 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 <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cytarabine" title="Learn more about cytarabine from ScienceDirect's AI-generated Topic Pages">cytarabine</a>, 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.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofPharmacological Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAML-
dc.subjectcyclopamine hydrate C4116 (Sigma)-
dc.subjectcytarabine PHR1787 (Sigma)-
dc.subjectDymetil sulfoxide D8418 (Sigma)-
dc.subjectGlasdegib PZ0303 (Sigma)-
dc.subjectHDAC6-
dc.subjectHedgehog-
dc.subjectPrimary cilium-
dc.subjectRoscovitine R7772 (Sigma)-
dc.subjectTubastatinA hydrochloride SML0044 (Sigma)-
dc.subjectZebrafish-
dc.titleHDAC6 inhibition decreases leukemic stem cell expansion driven by Hedgehog hyperactivation by restoring primary ciliogenesis-
dc.typeArticle-
dc.identifier.doi10.1016/j.phrs.2022.106378-
dc.identifier.scopuseid_2-s2.0-85136083900-
dc.identifier.volume183-
dc.identifier.eissn1096-1186-
dc.identifier.isiWOS:000844306400004-
dc.identifier.issnl1043-6618-

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