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Acute myeloid leukemia

Demethylator phenotypes in acute myeloid leukemia

Leukemia volume 32, pages 2178–2188 (2018)Cite this article

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Abstract

Acute myeloid leukemia (AML) often harbors mutations in epigenetic regulators, and also has frequent DNA hypermethylation, including the presence of CpG island methylator phenotypes (CIMPs). Although global hypomethylation is well known in cancer, the question of whether distinct demethylator phenotypes (DMPs) exist remains unanswered. Using Illumina 450k arrays for 194 patients from The Cancer Genome Atlas, we identified two distinct DMPs by hierarchical clustering: DMP.1 and DMP.2. DMP.1 cases harbored mutations in NPM1 (94%), FLT3 (71%) and DNMT3A (61%). Surprisingly, only 40% of patients with DNMT3A mutations were DMP.1, which has implications for mechanisms of transformation by this mutation. In contrast, DMP.2 AML was comprised of patients with t(8;21), inv(16) or t(15;17), suggesting common methylation defects connect these disparate rearrangements. RNA-seq revealed upregulated genes functioning in immune response (DMP.1) and development (DMP.2). We confirmed these findings by integrating independent 450k data sets (236 additional cases), and found prognostic effects by DMP status, independent of age and cytogenetics. The existence of DMPs has implications for AML pathogenesis and may augment existing tools in risk stratification.

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Acknowledgements

We would like to thank Drs. Humberto Ferreira and Manel Esteller for providing additional clinical data to supplement their 450k GEO submission.

Funding

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, 19140, USA

    Andrew D. Kelly, Jozef Madzo, Priyanka Madireddi, Charly R. Good, Jaroslav Jelinek & Jean-Pierre J. Issa

  2. Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    Patricia Kropf & Jean-Pierre J. Issa

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  1. Andrew D. Kelly
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Correspondence to Jean-Pierre J. Issa.

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Kelly, A.D., Madzo, J., Madireddi, P. et al. Demethylator phenotypes in acute myeloid leukemia. Leukemia 32, 2178–2188 (2018). https://doi.org/10.1038/s41375-018-0084-2

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