American Association for Cancer Research
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Supplementary Figure 2 from An miRNA–DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia

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posted on 2023-03-31, 19:21 authored by 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, Eric Wattel

DNMT1 protein expression in SKM1 AZA-sensitive (-S) versus AZA-resistant clones (-R). The Figure corresponds to the Figure 1B with signal quantification performed with ImageJ software. The data are expressed as mean {plus minus} SD of three independent experiments, with each performed in triplicate (Mann-Whitney test, p<0.05).

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ANR

ARC

Islamic Development Bank

Hospices Civils de Lyon and Lyon I University

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ARTICLE 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.

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