HDAC7 is a potential therapeutic target in acute erythroid leukemia.
Wenyu ZhangKeita YamamotoYu-Hsuan ChangTomohiro YabushitaYangying HaoRuka ShimuraJakushin NakaharaShiori ShikataKohei IidaQianyi ChenXichen ZhangToshio KitamuraSusumu GoyamaPublished in: Leukemia (2024)
Acute erythroleukemia (AEL) is a rare subtype of acute myeloid leukemia with a poor prognosis. In this study, we established a novel murine AEL model with Trp53 depletion and ERG overexpression. ERG overexpression in Trp53-deficient mouse bone marrow cells, but not in wild-type bone marrow cells, leads to AEL development within two months after transplantation with 100% penetrance. The established mouse AEL cells expressing Cas9 can be cultured in vitro, induce AEL in vivo even in unirradiated recipient mice, and enable efficient gene ablation using the CRISPR/Cas9 system. We also confirmed the cooperation between ERG overexpression and TP53 inactivation in promoting the growth of immature erythroid cells in human cord blood cells. Mechanistically, ERG antagonizes KLF1 and inhibits erythroid maturation, whereas TP53 deficiency promotes proliferation of erythroid progenitors. Furthermore, we identified HDAC7 as a specific susceptibility in AEL by the DepMap-based two-group comparison analysis. HDAC7 promotes the growth of human and mouse AEL cells both in vitro and in vivo through its non-enzymatic functions. Our study provides experimental evidence that TP53 deficiency and ERG overexpression are necessary and sufficient for the development of AEL and highlights HDAC7 as a promising therapeutic target for this disease.
Keyphrases
- induced apoptosis
- bone marrow
- cell cycle arrest
- crispr cas
- poor prognosis
- acute myeloid leukemia
- endothelial cells
- signaling pathway
- cell proliferation
- mesenchymal stem cells
- endoplasmic reticulum stress
- type diabetes
- oxidative stress
- stem cells
- wild type
- metabolic syndrome
- genome editing
- long non coding rna
- transcription factor
- acute lymphoblastic leukemia
- liver failure
- nitric oxide
- skeletal muscle
- adipose tissue
- histone deacetylase
- drug induced
- extracorporeal membrane oxygenation
- copy number
- mechanical ventilation
- aortic dissection
- clinical evaluation
- catheter ablation