A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex-Mediated DNA Replication.
Yue ShengJiangbo WeiFang YuHuanzhou XuChunjie YuQiong WuYin LiuLei LiXiao-Long CuiXueying GuBin ShenWei LiYong HuangSumita Bhaduri-McintoshChuan HeZhijian QianPublished in: Blood (2021)
YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in Acute Myeloid Leukemia (AML) and that it is required for proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We find that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem/progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs, but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides the compelling evidence to show an oncogenic role and a distinct mechanism of YTHDC1 in AML.
Keyphrases
- acute myeloid leukemia
- stem cells
- induced apoptosis
- allogeneic hematopoietic stem cell transplantation
- signaling pathway
- cell cycle arrest
- endothelial cells
- type diabetes
- oxidative stress
- gene expression
- dna methylation
- endoplasmic reticulum stress
- bone marrow
- acute lymphoblastic leukemia
- cell proliferation
- cell death
- adipose tissue
- pi k akt
- mesenchymal stem cells
- high fat diet induced
- induced pluripotent stem cells