Insufficiency of Non-Canonical PRC1 Complex Cooperates with an Activating JAK2 Mutation in the Pathogenesis of Myelofibrosis

Introduction: PcG proteins form two main multiprotein complexes, Polycomb repressive complex 1 (PRC1) and PRC2. They repress the transcription of target genes. Polycomb group ring finger protein1 (PCGF1) is a component of PRC1.1, a non-canonical PRC1.1 that monoubiquitylates H2A at lysine 119 in a manner independent of H3K27me3. Several groups including ours showed that the loss of Ezh2, a component of PRC2, promotes the development of JAK2 V617F-induced Myelofibrosis (MF) in mice. However, the role of PRC1.1 in hematologic malignancies is still not fully understood. We found that the deletion of PCGF1 in mice promotes myeloid commitment of hematopoietic stem and progenitor cells (HSPCs), and eventually induces a lethal myeloproliferative neoplasm (MPN)-like disease in mice (Nakajima-Takagi Y, unpublished data). Based on these findings, we investigated the role of PCGF1 in a mouse model of JAK2V617F-induced myelofibrosis. Methods: We transplanted BM cells from Cre-ERT2, PCGF1flox/flox;Cre-ERT2, JAK2V617F;Cre-ERT2, and JAK2V617F;PCGF1flox/flox;Cre-ERT2 mice into lethally irradiated recipient mice. We deleted PCGF1 by tamoxifen administration 4 weeks after transplantation. Results: JAK2/PCGF1 KO mice developed lethal MF significantly earlier than the other genotypes (p Conclusions: Our findings suggest that dysregulated PRC1.1 function promotes JAK2V617F-induced MF with mechanisms distinct from MF associated with PRC2 dysfunction. Disclosures Harada: Celgene: Research Funding.