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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
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 23(12)
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
Oncology
DNA (Cytosine-5-)-Methyltransferase 1
Male
Cancer Research
medicine.medical_specialty
Methyltransferase
Myeloid
Azacitidine
Biology
environment and public health
Disease-Free Survival
03 medical and health sciences
0302 clinical medicine
Internal medicine
microRNA
medicine
Humans
Aged
Aged, 80 and over
Myeloid leukemia
Cancer
Middle Aged
medicine.disease
Prognosis
Gene Expression Regulation, Neoplastic
Leukemia
Leukemia, Myeloid, Acute
MicroRNAs
030104 developmental biology
medicine.anatomical_structure
International Prognostic Scoring System
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Myelodysplastic Syndromes
embryonic structures
Immunology
Female
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 23
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....ef7003e39c1f8288d48c228270946c54