Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis
Mutations in genes involved in epigenetic regulation cooperate with the driver mutations of myeloproliferative neoplasms, including JAK2 mutations, and play a key role in the pathogenesis of primary myelofibrosis. We and other groups demonstrated that the loss of Ezh2, the histone methyltransferase of Polycomb repressive complex 2 (PRC2) frequently mutated in primary myelofibrosis, promotes the development of JAK2V617F-induced myelofibrosis in mice. Polycomb group ring finger protein1 (Pcgf1) is a component of PRC1.1, a non-canonical PRC1 that monoubiquitylates H2A at lysine 119 (H2AK119ub1) in a manner independent of PRC2. We herein investigated the impact of PRC1.1 insufficiency on myelofibrosis in mice. The deletion of Pcgf1 in JAK2V617F mice markedly promoted the development of myelofibrosis accompanied with a block in erythroid differentiation. Transcriptome and chromatin immunoprecipitation sequence analyses clearly showed de-repression of PRC1 target genes in hematopoietic progenitors in Pcgf1-deficient JAK2V617 mice and revealed Hoxa cluster genes as direct targets. The deletion of Pcgf1 in JAK2V617 HSPCs rescued attenuated proliferation of JAK2V617 progenitors in culture and overexpression of Hoxa9 did in a similar manner. Genes that were specifically activated in Ezh2-deficient JAK2V617 HSPCs, such as Hmga2, were not altered in expression in Pcgf1-deleted JAK2V617 progenitors. Our results reveal a tumor suppressor function of PRC1.1 in myelofibrosis and suggest that PRC1.1 insufficiency has a differential impact from that of PRC2 insufficiency in the pathogenesis of myelofibrosis.