PRC2 insufficiency causes p53-dependent dyserythropoiesis in myelodysplastic syndrome

• Published in: Leukemia 2021-04, Vol.35 (4), p.1156-1165
• Main Authors: Aoyama, Kazumasa, Shinoda, Daisuke, Suzuki, Emi, Nakajima-Takagi, Yaeko, Oshima, Motohiko, Koide, Shuhei, Rizq, Ola, Si, Sha, Tara, Shiro, Sashida, Goro, Iwama, Atsushi
• Format: Article
• Language: English
• Subjects: 38/91; 631/67; 631/67/1990/1673; 64/60; 96/2; Anemia; Animals; Apoptosis; Biomarkers; Biosynthesis; Bone marrow; Cancer Research; Care and treatment; Cells (biology); Cellular proteins; Chromatin Immunoprecipitation Sequencing; Clonal deletion; Critical Care Medicine; Deletion; Development and progression; Disease Models, Animal; Disease Susceptibility; DNA methylation; Erythroblasts; Erythroblasts - metabolism; Erythroblasts - pathology; Erythropoiesis - genetics; Flow Cytometry; Gene expression; Genetic aspects; Genomes; Health aspects; Hematology; Hematopoietic stem cells; Histones; Histones - metabolism; Humans; Intensive; Internal Medicine; Laboratory animals; Leukemia; MDM2 protein; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Models, Biological; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - diagnosis; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - therapy; Oncology; p53 Protein; Pathogenesis; Polycomb group proteins; Polycomb Repressive Complex 2 - genetics; Progenitor cells; Protein Binding; Stem cells; Transcription; Tumor Suppressor Protein p53 - metabolism; Ubiquitin; Ubiquitin-protein ligase
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-01023-1

EZH1 and EZH2 are enzymatic components of polycomb repressive complex (PRC) 2, which catalyzes histone H3K27 tri-methylation (H3K27me3) to repress the transcription of PRC2 target genes. We previously reported that the hematopoietic cell-specific Ezh2 deletion ( Ezh2 Δ/Δ ) induced a myelodysplastic syndrome (MDS)-like disease in mice. We herein demonstrated that severe PRC2 insufficiency induced by the deletion of one allele Ezh1 in Ezh2 -deficient mice ( Ezh1 +/− Ezh2 Δ/Δ ) caused advanced dyserythropoiesis accompanied by a differentiation block and enhanced apoptosis in erythroblasts. p53, which is activated by impaired ribosome biogenesis in del(5q) MDS, was specifically activated in erythroblasts, but not in hematopoietic stem or progenitor cells in Ezh1 +/− Ezh2 Δ/Δ mice. Cdkn2a , a major PRC2 target encoding p19 Arf , which activates p53 by inhibiting MDM2 E3 ubiquitin ligase, was de-repressed in Ezh1 +/− Ezh2 Δ/Δ erythroblasts. The deletion of Cdkn2a as well as p53 rescued dyserythropoiesis in Ezh1 +/− Ezh2 Δ/Δ mice, indicating that PRC2 insufficiency caused p53-dependent dyserythropoiesis via the de-repression of Cdkn2a . Since PRC2 insufficiency is often involved in the pathogenesis of MDS, the present results suggest that p53-dependent dyserythropoiesis manifests in MDS in the setting of PRC2 insufficiency.