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Acute Leukemias

CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

Leukemia volume 26, pages 244–254 (2012)Cite this article

Abstract

The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. The basis for these contrasting cell fates, and for selective CpG hypomethylation by decitabine, is poorly understood. Promoter CpGs, with methylation measured by microarray, were classified by the direction of methylation change with normal myeloid maturation. In AML cells, the methylation pattern at maturation-responsive CpGs suggested at least partial maturation. Consistent with partial maturation, in gene expression analyses, AML cells expressed high levels of the key lineage-specifying factor CEBPA, but relatively low levels of the key late-differentiation driver CEBPE. In methylation analysis by mass spectrometry, CEBPE promoter CpGs that are usually hypomethylated during granulocyte maturation were significantly hypermethylated in AML cells. Decitabine-induced hypomethylation was greatest at these and other promoter CpGs that are usually hypomethylated with myeloid maturation, accompanied by cellular differentiation of AML cells. In contrast, decitabine-treated normal HSCs retained immature morphology, and methylation significantly decreased at CpGs that are less methylated in immature cells. High expression of lineage-specifying factor and aberrant epigenetic repression of some key late-differentiation driver genes distinguishes AML cells from normal HSCs, and could explain the contrasting differentiation and methylation responses to decitabine.

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Acknowledgements

We acknowledge the assistance of Dr Ying Jiang for bioinformatics analysis and sample preparation, Dr Pieter Faber and the Cleveland Clinic Genomics Core for processing of samples and the following gifts: Mary Laughlin and Nick Greco at the Abraham J and Phyllis Katz Cord Blood Foundation and Cleveland Cord Blood Center for cord blood samples. YS is supported by NIH (1R01CA138858, U54HL090513), Department of Defense (PR081404). KPN is supported by Scott Hamilton CARES Foundation.

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Author notes

  1. S Negrotto and K P Ng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    S Negrotto, K P Ng, A M Jankowska, K Guinta, J Maciejewski & Y Saunthararajah

  2. Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH, USA

    J Bodo & E Hsi

  3. Department of Integrative Genomics Analysis, Genomics Medicine Institute, Cleveland Clinic, Cleveland, OH, USA

    B Gopalan

  4. Division of Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, OH, USA

    J C Mulloy

  5. Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    J Maciejewski & Y Saunthararajah

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Negrotto, S., Ng, K., Jankowska, A. et al. CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors. Leukemia 26, 244–254 (2012). https://doi.org/10.1038/leu.2011.207

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