Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cancer Cell. 2021 Jul 12;39(7):958-972.e8. doi: 10.1016/j.ccell.2021.04.017. Epub 2021 May 27.
N-Methyladenosine (mA) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How mA dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential mA reader in myeloid leukemia from a genome-wide CRISPR screen and that mA is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-mA condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect mA-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, mA is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.
mRNA 上的 N6-甲基腺苷（m6A）介导多种生物学过程，其失调与肿瘤发生有关。m6A 如何在白血病中决定其多样化的分子和细胞效应尚不清楚。我们通过全基因组 CRISPR 筛选发现，YTHDC1 是髓系白血病中必需的 m6A 读码器，并且 m6A 是 YTHDC1 发生液-液相分离并形成核 YTHDC1-m6A 凝聚物（nYAC）所必需的。与正常造血干细胞和祖细胞相比，急性髓系白血病（AML）细胞中的 nYAC 数量增加。AML 细胞需要 nYAC 来维持细胞存活和未分化状态，这对于白血病的维持至关重要。此外，nYAC 使 YTHDC1 能够保护 m6A-mRNAs 免受 PAXT 复合物和外泌体相关 RNA 降解的影响。总之，m6A 是由相分离介导的核体形成所必需的，该核体维持 mRNA 的稳定性并控制癌细胞的存活和分化。
