Jarid2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells

How specific genetic lesions contribute to transformation of non-malignant myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) are poorly understood. The JARID2 gene is lost by chromosomal deletions in a proportion of MPN/MDS patients who progress to sAML. In this study, genetic mouse models and patient-derived xenografts (PDX) demonstrated that Jarid2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either reduced overall survival of MPN, 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 new therapeutic targets. Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) were sorted from Vav-CRE: Control and Vav-CRE:Jarid2-KO or Mx1-CRE: Control, Mx1-CRE: Jarid2-KO, and Max1-CRE: Jarid2-KO - Jak2-V617F mice for RNA-seq to determine gene expression. Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) were sorted from Vav-CRE: Control and Vav-CRE:Jarid2-KO to determine H3K27me3 chromatin profile by ChIPmentation.