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Myelodysplasias

Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells

Leukemia volume 27, pages 2177–2186 (2013)Cite this article

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Abstract

The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 3 lysine 4 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq (chromatin immunoprecipitation coupled with whole genome sequencing) analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in nuclear factor (NF)-κB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrate that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-κB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.

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Acknowledgements

This work was supported by Grant RP100202 from the Cancer Prevention and Research Institute of Texas (CPRIT), the Ruth and Ken Arnold Fund (GGM), the MD Anderson Cancer Center Leukemia SPORE grant CA100632 and the MD Anderson Cancer Center CCSG CA016672. IG-G was funded by the Regional Ministry of Education of Castilla-la Mancha, Spain, supported by the European Social Fund (ESF). We are thankful for the efforts from Dr Hui Yao, Dr Lixia Diao and Dr Jing Wang (Department of Bioinformatics and Computational Biology, MDACC) for initial analysis of CHIP-Seq data. We are also thankful to Dr Sean Post and Dr Zeev Estrov for critical reading of the manuscript.

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Authors and Affiliations

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

    Y Wei, S Dimicoli, S Pierce, H Yang, Y Jia, H Zheng, Z Fang, I Ganan-Gomez, H Kantarjian & G Garcia-Manero

  2. Department of Human Genetics, Baylor College of Medicine, Houston, TX, USA

    R Chen & H Wang

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

    C Bueso-Ramos & M Nguyen

  4. Dana-Farber Cancer Institute, Boston, MA, USA

    D Neuberg

  5. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Alcala, Alcala de Henares, Spain

    I Ganan-Gomez

  6. Brigham and Women’s Hospital, Boston, MA, USA

    B Ebert

  7. Department of Leukemia and Human Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    R Levine

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Wei, Y., Chen, R., Dimicoli, S. et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia 27, 2177–2186 (2013). https://doi.org/10.1038/leu.2013.91

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