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Personalized Medicine and Imaging

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, Catherine Koering, Aminetou Mint Mohamed, Delphine Maucort-Boulch, Guillaume Robert, Patrick Auberger, Pascale Flandrin-Gresta, Lionel Adès, Pierre Fenaux, Olivier Kosmider, Emmanuelle Tavernier-Tardy, Jérôme Cornillon, Denis Guyotat, Lydia Campos, Franck Mortreux and Eric Wattel
Françoise Solly
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.
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Catherine Koering
CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS – HCL, Université Lyon 1, Pierre Bénite, France.
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Aminetou Mint Mohamed
CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS – HCL, Université Lyon 1, Pierre Bénite, France.
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Delphine Maucort-Boulch
Service de Biostatistique, UMR 5558, Laboratoire Biostatistique Santé, Pierre-Bénite, France.
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Guillaume Robert
INSERM U1065, Centre Mediterranéen de Médecine Moléculaire, Team «Cell Death, Differentiation, Inflammation and Cancer», Nice, France.
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Patrick Auberger
INSERM U1065, Centre Mediterranéen de Médecine Moléculaire, Team «Cell Death, Differentiation, Inflammation and Cancer», Nice, France.
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Pascale Flandrin-Gresta
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.
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Lionel Adès
Service d'hématologie, Hôpital St Louis (Assistance Publique Hôpitaux de Paris) and Paris 7 University, Paris, France.
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Pierre Fenaux
Service d'hématologie, Hôpital St Louis (Assistance Publique Hôpitaux de Paris) and Paris 7 University, Paris, France.
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Olivier Kosmider
Institut de Cancérologie de la Loire, Saint Priest en Jarez, France.
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Emmanuelle Tavernier-Tardy
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.
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Jérôme Cornillon
Service d’Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Broca-Cochin-Hôtel-Dieu, Paris, France.
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Denis Guyotat
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.
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Lydia Campos
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.
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Franck Mortreux
CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS – HCL, Université Lyon 1, Pierre Bénite, France.
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Eric Wattel
CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS – HCL, Université Lyon 1, Pierre Bénite, France.Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Université Lyon I, Pierre Bénite, France.
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  • For correspondence: eric.wattel@ens-lyon.fr
DOI: 10.1158/1078-0432.CCR-16-2304
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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; 1–10. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received September 15, 2016.
  • Revision received November 2, 2016.
  • Accepted November 5, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst March 17, 2017
doi: 10.1158/1078-0432.CCR-16-2304

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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, Catherine Koering, Aminetou Mint Mohamed, Delphine Maucort-Boulch, Guillaume Robert, Patrick Auberger, Pascale Flandrin-Gresta, Lionel Adès, Pierre Fenaux, Olivier Kosmider, Emmanuelle Tavernier-Tardy, Jérôme Cornillon, Denis Guyotat, Lydia Campos, Franck Mortreux and Eric Wattel
Clin Cancer Res March 17 2017 DOI: 10.1158/1078-0432.CCR-16-2304

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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, Catherine Koering, Aminetou Mint Mohamed, Delphine Maucort-Boulch, Guillaume Robert, Patrick Auberger, Pascale Flandrin-Gresta, Lionel Adès, Pierre Fenaux, Olivier Kosmider, Emmanuelle Tavernier-Tardy, Jérôme Cornillon, Denis Guyotat, Lydia Campos, Franck Mortreux and Eric Wattel
Clin Cancer Res March 17 2017 DOI: 10.1158/1078-0432.CCR-16-2304
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