Insufficiency of polycomb repressive complex 2 (PRC2), which trimethylates histone H3 at lysine 27, is frequently found in primary myelofibrosis and promotes the development of JAK2V617F-induced myelofibrosis in mice by enhancing the production of dysplastic megakaryocytes. Polycomb group ring finger protein 1 (Pcgf1) is a component of PRC1.1, a non-canonical PRC1 that monoubiquitylates H2A at lysine 119 (H2AK119ub1). We herein investigated the impact of PRC1.1 insufficiency on myelofibrosis. The deletion of Pcgf1 in JAK2V617F mice strongly promoted the development of lethal myelofibrosis accompanied by a block in erythroid differentiation. Transcriptome and chromatin immunoprecipitation sequence analyses showed the de-repression of PRC1.1 target genes in Pcgf1-deficient JAK2V617F hematopoietic progenitors and revealed Hoxa cluster genes as direct targets. The deletion of Pcgf1 in JAK2V617F hematopoietic stem and progenitor cells (HSPCs), as well as the overexpression of Hoxa9, restored the attenuated proliferation of JAK2V617F progenitors. The overexpression of Hoxa9 also enhanced JAK2V617F-mediated myelofibrosis. The expression of PRC2 target genes identified in PRC2-insufficient JAK2V617F HSPCs was not largely altered in Pcgf1-deleted JAK2V617F HSPCs. The present results revealed a tumor suppressor function for PRC1.1 in myelofibrosis and suggest that PRC1.1 insufficiency has a different impact from that of PRC2 insufficiency on the pathogenesis of myelofibrosis.

在原发性骨髓纤维化中经常发现多梳抑制复合物 2 (PRC2) 的不足，它在 27 位赖氨酸处对组蛋白 H3 进行三甲基化，并通过增强发育不良巨核细胞的产生促进 JAK2V617F 诱导的小鼠骨髓纤维化的发展。Polycomb 组无名指蛋白 1 (Pcgf1) 是 PRC1.1 的一个组成部分，PRC1.1 是一种非规范的 PRC1，可在 119 位赖氨酸 (H2AK119ub1) 处单泛素化 H2A。我们在此研究了 PRC1.1 不足对骨髓纤维化的影响。JAK2V617F 小鼠中Pcgf1的缺失强烈促进了致死性骨髓纤维化的发展，伴随着红系分化的阻滞。转录组和染色质免疫沉淀序列分析显示 Pcgf1 中 PRC1.1 靶基因的去抑制-缺陷的 JAK2V617F 造血祖细胞并揭示了Hoxa簇基因作为直接靶标。JAK2V617F 造血干细胞和祖细胞 (HSPC) 中 Pcgf1的缺失以及Hoxa9的过表达恢复了 JAK2V617F 祖细胞的减毒增殖。Hoxa9的过表达也增强了 JAK2V617F 介导的骨髓纤维化。在PRC2不足的JAK2V617F HSPC中鉴定的PRC2靶基因的表达在Pcgf1缺失的JAK2V617F HSPC中没有显着改变。目前的结果揭示了PRC1.1在骨髓纤维化中的肿瘤抑制功能，并表明PRC1.1功能不全与PRC2功能不全对骨髓纤维化发病机制的影响不同。