Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis

• Published in: Leukemia 2022-02, Vol.36 (2), p.452-463
• Main Authors: Shinoda, Daisuke, Nakajima-Takagi, Yaeko, Oshima, Motohiko, Koide, Shuhei, Aoyama, Kazumasa, Saraya, Atsunori, Harada, Hironori, Rahmutulla, Bahityar, Kaneda, Atsushi, Yamaguchi, Kiyoshi, Furukawa, Yoichi, Koseki, Haruhiko, Shimoda, Kazuya, Tanaka, Tomoaki, Sashida, Goro, Iwama, Atsushi
• Format: Article
• Language: English
• Subjects: 45/15; 45/41; 631/67/1990/2331; 692/699/1541/1990/2331; Animals; Cancer Research; Cell Differentiation; Cells (biology); Chromatin; Critical Care Medicine; Deletion; Epigenetics; Experiments; Female; Flow cytometry; Gene expression; Genes; Hematology; Hematopoietic stem cells; Histone H3; Histones; Immunoprecipitation; Intensive; Internal Medicine; Janus Kinase 2 - genetics; Laboratory animals; Leukemia; Lysine; Male; Medicine; Medicine & Public Health; Megakaryocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoclonal antibodies; Mutation; Myelofibrosis; Oncology; Pathogenesis; Polycomb group proteins; Polycomb Repressive Complex 1 - physiology; Primary Myelofibrosis - etiology; Primary Myelofibrosis - metabolism; Primary Myelofibrosis - pathology; Progenitor cells; Proteins; RING finger proteins; Rings (mathematics); Stem cells; Transcriptomes; Tumor suppressor genes; Tumors; Ubiquitination
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01402-2

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.