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Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.

ABSTRACT: Hypomethylating agents are widely used in patients with myelodysplastic syndromes and unfit patients with acute myeloid leukemia. However, it is not well understood why only some patients respond to hypomethylating agents. We found previously that the effect of decitabine on hematopoietic stem cell viability differed between Mll5 wild-type and null cells. We, therefore, investigated the role of MLL5 expression levels on outcome of acute myeloid leukemia patients who were treated with decitabine. MLL5 above the median expression level predicted longer overall survival independent of DNMT3A mutation status in bivariate analysis (median overall survival for high vs. low MLL5 expression 292 vs. 167 days; P=0.026). In patients who received three or more courses decitabine, high MLL5 expression and wild-type DNMT3A independently predicted improved overall survival (median overall survival for high vs. low MLL5 expression 468 vs. 243 days; P=0.012). In transformed murine cells, loss of Mll5 was associated with resistance to low-dose decitabine, less global DNA methylation in promoter regions, and reduced DNA demethylation upon decitabine treatment. Together, these data support our clinical observation of improved outcome in decitabine-treated patients who express MLL5 at high levels, and suggest a mechanistic role of MLL5 in the regulation of DNA methylation.

SUBMITTER: Yun H

PROVIDER: S-EPMC4562534 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.

Yun Haiyang H Damm Frederik F Yap Damian D Schwarzer Adrian A Chaturvedi Anuhar A Jyotsana Nidhi N Lübbert Michael M Bullinger Lars L Döhner Konstanze K Geffers Robert R Aparicio Samuel S Humphries R Keith RK Ganser Arnold A Heuser Michael M

Haematologica 20140603 9

Hypomethylating agents are widely used in patients with myelodysplastic syndromes and unfit patients with acute myeloid leukemia. However, it is not well understood why only some patients respond to hypomethylating agents. We found previously that the effect of decitabine on hematopoietic stem cell viability differed between Mll5 wild-type and null cells. We, therefore, investigated the role of MLL5 expression levels on outcome of acute myeloid leukemia patients who were treated with decitabine. ...[more]

PMID: 24895338

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Project description:BackgroundDespite its inconsistent response rate, decitabine, a demethylating agent, is often used as a non-intensive alternative therapeutic agent for acute myeloid leukemia (AML). It has been reported that relapsed/refractory AML patients with t(8;21) translocation achieved better clinical outcomes with a decitabine-based combination regimen than other AML subtypes; however, the mechanisms underlying this phenomenon remain unknown. Herein, the DNA methylation landscape of de novo patients with the t(8;21) translocation was compared with that of patients without the translocation. Moreover, the methylation changes induced by decitabine-based combination regimens in de novo/complete remission paired samples were investigated to elucidate the mechanisms underlying the better responses observed in t(8;21) AML patients treated with decitabine.MethodsThirty-three bone marrow samples from 28 non-M3 AML patients were subjected to DNA methylation sequencing to identify the differentially methylated regions and genes of interest. TCGA-AML Genome Atlas-AML transcriptome dataset was used to identify decitabine-sensitive genes that were downregulated following exposure to a decitabine-based regimen. In addition, the effect of decitabine-sensitive gene on cell apoptosis was examined in vitro using Kasumi-1 and SKNO-1 cells.ResultsA total of 1377 differentially methylated regions that specifically responsive to decitabine in t(8;21) AML were identified, of which 210 showed hypomethylation patterns following decitabine treatment aligned with the promoter regions of 72 genes. And the methylation-silencing genes, LIN7A, CEBPA, BASP1, and EMB were identified as critical decitabine-sensitive genes in t(8;21) AML. Moreover, AML patients with hypermethylated LIN7A and reduced LIN7A expression had poor clinical outcomes. Meanwhile, the downregulation of LIN7A inhibited decitabine/cytarabine combination treatment-induced apoptosis in t(8;21) AML cells in vitro.ConclusionThe findings of this study suggest that LIN7A is a decitabine-sensitive gene in t(8;21) AML patients that may serve as a prognostic biomarker for decitabine-based therapy.

Dataset Information

Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.

Publications

Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.

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