An miRNA–DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Clinical Cancer Research Année : 2017

An miRNA–DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia

Françoise Solly
  • Fonction : Auteur
Catherine Koering
  • Fonction : Auteur
Aminetou Mint Mohamed
  • Fonction : Auteur
Guillaume Robert
  • Fonction : Auteur
Patrick Auberger
  • Fonction : Auteur
Pascale Flandrin-Gresta
  • Fonction : Auteur
Lionel Adès
Pierre Fenaux
  • Fonction : Auteur
Olivier Kosmider
  • Fonction : Auteur
Emmanuelle Tavernier-Tardy
  • Fonction : Auteur
Jérôme Cornillon
  • Fonction : Auteur
Denis Guyotat
  • Fonction : Auteur
Lydia Campos
  • Fonction : Auteur
Franck Mortreux
  • Fonction : Auteur
Eric Wattel
  • Fonction : Auteur

Résumé

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 resistance in vitro. We 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 that in silico targeted 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*low myelodysplastic 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.

Dates et versions

hal-04152040 , version 1 (05-07-2023)

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Citer

Françoise Solly, Catherine Koering, Aminetou Mint Mohamed, Delphine Maucort-Boulch, Guillaume Robert, et al.. An miRNA–DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia. Clinical Cancer Research, 2017, 23 (12), pp.3025-3034. ⟨10.1158/1078-0432.CCR-16-2304⟩. ⟨hal-04152040⟩

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