title: An miRNA-DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia.
abstract: Purpose:Azacitidine inhibits DNA methyltransferases, including DNMT1, and is currently the standard of care for patients with higher-risk myelodysplastic syndrome (HRMDS) or low blast count acute myeloid leukemia (AML).Experimental Design:The expression of 754 miRNAs was compared in azacitidine-resistant and azacitidine-sensitive myelodysplastic syndrome cells. We investigated the role of differentially expressed miRNAs on DNMT1 expression and azacitidine resistancein vitroWe next evaluated anti-DNMT1 miRNA expression in pretreatment bone marrow samples derived from 75 patients treated with azacitidine for HRMDS or AML.Results:Seven miRNAs, including 5 thatin silicotargeted the DNMT1 3' UTR, were repressed in azacitidine-resistant cells in which DNMT1 protein levels were significantly higher. Ectopic anti-DNMT1 miRNA expression decreased DNMT1 expression and increased azacitidine sensitivity, whereas specific inhibition of endogenous anti-DNMT1 miRNAs increased DNMT1 expression and triggered azacitidine resistance. In patients treated with azacitidine, decreased expression of anti-DNMT1 miRNAs was associated with poor outcome. miR-126* had the strongest prognostic impact. Patients with miR-126*lowmyelodysplastic syndrome had significantly lower response rates (P= 0.04) and higher relapse rates (P= 0.03), as well as shorter progression-free (PFS;P= 0.004) and overall survival (OS;P= 0.004). Multivariate analysis showed that age, miR-126* expression, and revised International Prognostic Scoring System risk independently predicted PFS and OS. In 15 patient samples collected over time, decreased miRNA expression levels were associated with secondary resistance.Conclusions:A decreased expression of anti-DNMT1 miRNAs might account for azacitidine resistance in HRMDS and AML, and measuring miRNA expression before and during treatment might help predict primary or secondary azacitidine resistance.Clin Cancer Res; 23(12); 3025-34. ©2016 AACR.
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.|Laboratoire d'Hématologie, CHU de Saint-Etienne, Université de Saint Etienne, Saint Etienne, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Solly
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Koering
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.
authors.forename: Aminetou Mint
authors.initials: AM
authors.lastname: Mohamed
authors.affiliation: Service de Biostatistique, UMR 5558, Laboratoire Biostatistique Santé, Pierre-Bénite, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Maucort-Boulch
authors.affiliation: INSERM U1065, Centre Mediterranéen de Médecine Moléculaire, Team «Cell Death, Differentiation, Inflammation and Cancer», Nice, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.affiliation: INSERM U1065, Centre Mediterranéen de Médecine Moléculaire, Team «Cell Death, Differentiation, Inflammation and Cancer», Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.|Laboratoire d'Hématologie, CHU de Saint-Etienne, Université de Saint Etienne, Saint Etienne, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Flandrin-Gresta
authors.affiliation: Service d'hématologie, Hôpital St Louis (Assistance Publique Hôpitaux de Paris) and Paris 7 University, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Adès
authors.affiliation: Service d'hématologie, Hôpital St Louis (Assistance Publique Hôpitaux de Paris) and Paris 7 University, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Institut de Cancérologie de la Loire, Saint Priest en Jarez, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.|Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Broca-Cochin-Hôtel-Dieu, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tavernier-Tardy
authors.affiliation: Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Broca-Cochin-Hôtel-Dieu, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cornillon
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.|Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Broca-Cochin-Hôtel-Dieu, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Guyotat
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.|Laboratoire d'Hématologie, CHU de Saint-Etienne, Université de Saint Etienne, Saint Etienne, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Campos
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux
authors.affiliation: CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Université Lyon 1, Pierre Bénite, France. eric.wattel@ens-lyon.fr.|Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Université Lyon I, Pierre Bénite, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000008:administration & dosage; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction
chemical_list: D035683:MicroRNAs; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D001374:Azacitidine