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Myelodysplasias

Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies

Leukemia volume 27, pages 1301–1309 (2013)Cite this article

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Abstract

Polycomb repressive complex 2 (PRC2) is involved in trimethylation of histone H3 lysine 27 (H3K27), chromatin condensation and transcriptional repression. The silencing function of PRC2 complex is mostly attributed to its intrinsic activity for methylating H3K27. Unlike in B-cell lymphomas, enhancer of zeste homolog 2 (EZH2) mutations in myeloid malignancies are inactivating/hypomorphic. When we assessed the mutational status in myeloid malignancies (N=469 cases examined), we found EZH2 and EED/SUZ12 mutations in 8% and 3.3% of cases, respectively. In addition to mutant cases, reduced EZH2 expression was also found in 78% cases with hemizygous deletion (−7/del7q cases involving EZH2 locus) and 41% of cases with diploid chromosome 7, most interestingly cases with spliceosomal mutations (U2AF1/SRSF2 mutations; 63% of cases). EZH2 mutations were characterized by decreased H3K27 trimethylation and increased chromatin relaxation at specific gene loci accompanied by higher transcriptional activity. One of the major downstream target is HOX gene family, involved in the regulation of stem cell self-renewal. HOXA9 was found to be overexpressed in cases with decreased EZH2 expression either by EZH2/spliceosomal mutations or because of −7/del7q. In summary, our results suggest that loss of gene repression through a variety of mutations resulting in reduced H3K27 trimethylation may contribute to leukemogenesis.

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Acknowledgements

This work was supported in part by RO1HL-082983, K24 HL-077522, by a grant from the AA&MDS International Foundation and Robert Duggan Charitable Fund (JPM), and a grant from the Scott Hamilton Charitable Fund (HM). The results presented here are partly based on the data generated by the Cancer Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and The investigators and institutions who constitutes the TCGA research network can be found at http://cancergenome.nih.gov.

Author contributions

SNK designed the study, performed experiments, data collection, data interpretation and wrote the manuscript; AMJ, ZH, RM, NH and AJD performed experiments and wrote the manuscript; VC, SV, BP and CO performed experiments and edited the manuscript; YSu and YSa designed the experiments; FJR, ARM, MAS, AFL and MAM designed the study, data collection and wrote the manuscript. JPM and HM were responsible for overall study design, data collection, data interpretation and preparation of the manuscript. All authors approved the final version of the manuscript and the submission.

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Authors and Affiliations

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

    S N Khan, A M Jankowska, R Mahfouz, A J Dunbar, Y Sugimoto, N Hosono, Z Hu, V Cheriyath, S Vatolin, B Przychodzen, F J Reu, Y Saunthararajah, C O'Keefe, J P Maciejewski & H Makishima

  2. Department of Hematologic Oncology and Blood Disorders, Leukemia Program, Cleveland Clinic, Cleveland, OH, USA

    F J Reu, Y Saunthararajah, M A Sekeres & J P Maciejewski

  3. Department of Hematologic Malignancies, Lee H Moffitt Cancer Center, Tampa, FL, USA

    A F List

  4. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A R Moliterno & M A McDevitt

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Khan, S., Jankowska, A., Mahfouz, R. et al. Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies. Leukemia 27, 1301–1309 (2013). https://doi.org/10.1038/leu.2013.80

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