3016 - JARID2 Restricts Self-Renewal Capacity in Hematopoietic Progenitors and is A Myeloid Tumor Suppressor

Abstract

The most common genetic mutations in myeloproliferative neoplasms (MPN) occur in JAK2, MPL and CALR, while additional mutations in genes such as TET2, IDH1/2, and NRAS drive transformation to secondary acute myeloid leukemia (sAML). Genome sequencing studies identified chromosomal deletions of JARID2, a Polycomb Repressive Complex 2 (PRC2) co-factor, in post-MPN sAML. To investigate Jarid2 as a tumor suppressor, we utilized an inducible mouse model of Jak2V617F combined with floxed alleles of Jarid2 and the inducible Mx1-CRE. The absence of Jarid2 accelerated MPN, with a median survival of 23 and 43 days post Jarid2-deletion for Jarid2-/–Jak2V617F/ + and Jarid2+/–Jak2V617F/ + mice respectively, compared to 113-days for Jak2V617F/ + control mice. These data establish Jarid2 as a bona fide tumor suppressor in MPN. To understand the tumor suppressor role of Jarid2, we defined its role in normal hematopoiesis. Transplantation of hematopoietic stem cells (HSCs) or whole bone marrow (WBM) showed a striking difference. Vav-CRE:Jarid2-KO HSCs did not contribute to peripheral blood (PB) chimerism, whereas Vav-CRE:Jarid2-KO WBM contributed to PB lineages at levels comparable to control WBM. These data suggested that a population of cell(s) other than HSCs contributes to hematopoiesis in the absence of Jarid2. Strikingly, Vav-CRE:Jarid2-KO multipotent progenitors (MPPs) engrafted in primary and secondary recipients, generating tri-lineage hematopoiesis effectively. Additionally, MPPs from Jak2V617FJarid2KO mice can propagate MPN, unlike MPPs transplanted from Jak2V617F mice. RNA-seq analysis revealed upregulation of Runx1t1 and Mycn in Jarid2-KO MPPs, genes which can reprogram mature blood cells to a multipotent state, which was associated with depletion of H3K27me3. Expression of Runx1t1 and Mycn in wild-type MPPs endowed long-term repopulating capacity in vivo, phenocopying Jarid2-KO MPPs. Our data suggest that the biological role of Jarid2 in hematopoiesis is to restrict self-renewal capacity in lineage-committed progenitor cells, and that dysregulation of this process can contribute to hematopoietic malignancies.