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PRC2 insufficiency causes p53-dependent dyserythropoiesis in myelodysplastic syndrome
- Source :
- Leukemia. 35:1156-1165
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- 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 (Ezh2Δ/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+/-Ezh2Δ/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+/-Ezh2Δ/Δ mice. Cdkn2a, a major PRC2 target encoding p19Arf, which activates p53 by inhibiting MDM2 E3 ubiquitin ligase, was de-repressed in Ezh1+/-Ezh2Δ/Δ erythroblasts. The deletion of Cdkn2a as well as p53 rescued dyserythropoiesis in Ezh1+/-Ezh2Δ/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.
- Subjects :
- 0301 basic medicine
Cancer Research
biology
Chemistry
EZH2
macromolecular substances
Hematology
Molecular biology
Ubiquitin ligase
Pathogenesis
03 medical and health sciences
Haematopoiesis
030104 developmental biology
0302 clinical medicine
Histone
Oncology
hemic and lymphatic diseases
030220 oncology & carcinogenesis
biology.protein
Mdm2
Progenitor cell
PRC2
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi...........21d8c218ceaf3e094625cdf8ec13f5c6