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ANIMAL MODELS

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

Abstract

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.

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Fig. 1: Loss of Pcgf1 promoted the development of lethal myelofibrosis in JAK2V617F mice.
Fig. 2: Loss of Pcgf1 enhanced myelofibrosis in JAK2V617F mice.
Fig. 3: Loss of Pcgf1 in JAK2V617F mice induced dyserythropoiesis.
Fig. 4: Pcgf1 loss activated the myeloid gene signature in progenitor cells.
Fig. 5: Pcgf1 loss reduced H2AK119ub1 levels at myeloid-related genes.
Fig. 6: Hoxa cluster genes were derepressed in JAK2V617FPcgf1Δ/Δ progenitors.
Fig. 7: Pcgf1 loss augmented the proliferative capacity of JAK2V617FPcgf1Δ/Δ HSPCs.

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Acknowledgements

We would like to thank Ola Rizq for the critical review of our manuscript. The super-computing resource was provided by the Human Genome Center, the Institute of Medical Science, the University of Tokyo. This work was supported in part by Grants-in-Aid for Scientific Research (JP19H05653), Scientific Research on Innovative Areas “Replication of Non-Genomic Codes” (JP19H05746) from MEXT, Japan.

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DS performed the experiments, analyzed the results, made the figures, and actively wrote the manuscript; YN-T, MO, SK, KA, AS, HH, BR, AK, KY, YF, and GS assisted with the experiments; HK and KS provided mice; TT conceptualized the research and edited the manuscript; AI conceived of and directed the project, secured funding, and actively wrote the manuscript.

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Correspondence to Atsushi Iwama.

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Shinoda, D., Nakajima-Takagi, Y., Oshima, M. et al. Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis. Leukemia (2021). https://doi.org/10.1038/s41375-021-01402-2

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