JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells

Hamza Celik, Won Kyun Koh, Ashley C. Kramer, Elizabeth L. Ostrander, Cates Mallaney, Daniel A.C. Fisher, Jingyu Xiang, William C. Wilson, Andrew Martens, Alok Kothari, Gregory Fishberger, Eric Tycksen, Darja Karpova, Eric J. Duncavage, Youngsook Lee, Stephen T. Oh, Grant A. Challen

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Abstract

How specific genetic lesions contribute to transformation of non-malignant myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs) to secondary acute myeloid leukemia (sAML) are poorly understood. JARID2 is lost by chromosomal deletions in a proportion of MPN/MDS cases that progress to sAML. In this study, genetic mouse models and patient-derived xenografts demonstrated that JARID2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either reduced overall survival of animals with MPNs or drove transformation to sAML, depending on the timing and context of co-operating mutations. Mechanistically, JARID2 recruits PRC2 to epigenetically repress self-renewal pathways in hematopoietic progenitor cells. These studies establish JARID2 as a bona fide hematopoietic tumor suppressor and highlight potential therapeutic targets. JARID2 is recurrently deleted in acute myeloid leukemia progressed from myeloproliferative neoplasms and myelodysplastic syndromes. Celik et al. show that JARID2 recruits PRC2 to repress the expression of self-renewal networks, of which Mycn and Runx1t1 are important factors, in hematopoietic progenitor cells.

Original languageEnglish
Pages (from-to)741-756.e8
JournalCancer Cell
Volume34
Issue number5
DOIs
StatePublished - Nov 12 2018

Keywords

  • JARID2
  • myelodysplastic syndromes
  • myeloproliferative neoplasms
  • polycomb repressive complex 2
  • secondary acute myeloid leukemia

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    Celik, H., Koh, W. K., Kramer, A. C., Ostrander, E. L., Mallaney, C., Fisher, D. A. C., Xiang, J., Wilson, W. C., Martens, A., Kothari, A., Fishberger, G., Tycksen, E., Karpova, D., Duncavage, E. J., Lee, Y., Oh, S. T., & Challen, G. A. (2018). JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells. Cancer Cell, 34(5), 741-756.e8. https://doi.org/10.1016/j.ccell.2018.10.008