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Acute myeloid leukemia

A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome

Leukemia volume 31, pages 2011–2019 (2017)Cite this article

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Abstract

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP+). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP+=not reached, CIMP-=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP+=2.34, A-CIMP-=1.00; P=0.01). Hypermethylation in A-CIMP+ favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP+ was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP+ function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP+ AML should be validated prospectively.

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Gene Expression Omnibus

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Acknowledgements

This work was supported by National Institutes of Health grants R01CA158112 and P50CA100632. J-PJI. is an American Cancer Society Clinical Research professor supported by a generous gift from the FM Kirby Foundation.

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Authors and Affiliations

  1. Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

    A D Kelly, J Yamazaki, S Yu, J T Lee, B Patel, M Cesaroni, J Jelinek & J-PJ Issa

  2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Kroeger, J Yamazaki, R Taby, F Neumann, R He, S Liang, Y Lu, S A Pierce, S M Kornblau, F Ravandi, H M Kantarjian, J Jelinek & J-PJ Issa

  3. Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    Y Li

  4. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C E Bueso-Ramos

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  1. A D Kelly
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Kelly, A., Kroeger, H., Yamazaki, J. et al. A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome. Leukemia 31, 2011–2019 (2017). https://doi.org/10.1038/leu.2017.12

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