Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
22
01
2021
accepted:
26
08
2021
revised:
19
08
2021
pubmed:
10
9
2021
medline:
16
2
2022
entrez:
9
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34497325
doi: 10.1038/s41375-021-01402-2
pii: 10.1038/s41375-021-01402-2
doi:
Substances chimiques
Pcgf1 protein, mouse
0
Polycomb Repressive Complex 1
EC 2.3.2.27
Jak2 protein, mouse
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
452-463Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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