JARID2 Is a Tumor Suppressor in Myeloid Neoplasms

Myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) are nonmalignant blood disorders that progress to secondary acute myeloid leukemia (sAML) in a substantial portion of patients. A number of mutations have been identified that are associated with malignant progression, but the mechanisms underlying transformation have not been well characterized. Deletions involving JARID2, which encodes a cofactor of the polycomb repressive complex 2 (PRC2), occur in up to 6.5% of sAMLs, but not in de novo AML, raising the possibility that JARID2 loss might be an sAML-specific transforming event. To investigate the function of JARID2 in normal and malignant hematopoiesis, Celik and colleagues generated mice with inducible deletion of Jarid2 in hematopoietic stem cells (HSC). IDH2^R140Q mutations have been reported to precede JARID2 deletion in patients, and mice with IDH2^R140Q expression and Jarid2 deletion succumbed to AML, whereas mice with IDH2^R140Q without Jarid2 loss developed myeloproliferative disorder, indicating that JARID2 is a hematopoietic tumor suppressor. Jarid2 loss depleted primitive hematopoietic progenitor cells and disrupted differentiation and proliferation of HSCs. In contrast, Jarid2 loss enhanced self-renewal in multipotent progenitor cells (MPP). As JARID2 is responsible for recruiting PRC2 to establish H3K27me3, Jarid2 deletion was associated with loss of H3K27me3 in gene bodies that resulted in upregulation of HSC-identity genes including Mycn and Runx1t1. Expression of MYCN and RUNX1T1 was sufficient to phenocopy Jarid2 loss, promoting MPP self-renewal. In patient-derived MPN cells, JARID2 depletion enhanced self-renewal of HSCs and increased bone marrow engraftment and myelofibrosis in patient-derived xenografts. Taken together, these findings reveal that JARID2 is a hematopoietic tumor suppressor that restricts self-renewal of MPPs to suppress the transformation of MPNs and MDSs to sAML.

Celik H, Koh WK, Kramer AC, Ostrander EL, Mallaney C, Fisher DAC, et al. JARID2 functions as a tumor suppressor in myeloid neoplasms by repressing self-renewal in hematopoietic progenitor cells. Cancer Cell 2018;34:741–56.

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