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Cancer Cell. 2018 Nov 12;34(5):741-756.e8. doi: 10.1016/j.ccell.2018.10.008.

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

Author information

1
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Genome Technology Access Center, Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
5
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
7
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Developmental, Regenerative and Stem Cell Biology Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: gchallen@dom.wustl.edu.

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.

KEYWORDS:

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

PMID:
30423295
PMCID:
PMC6237100
[Available on 2019-11-12]
DOI:
10.1016/j.ccell.2018.10.008

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