生物
细胞生物学
白血病
核糖核酸
癌症研究
分子生物学
融合蛋白
作者
Tiffany M. Tran,Julia Philipp,Jaspal Bassi,Neha Nibber,Jolene M. Draper,Tasha L. Lin,Jayanth Kumar Palanichamy,Amit Kumar Jaiswal,Oscar Silva,May Paing,J. King,Sol Katzman,Jeremy R. Sanford,Dinesh S. Rao
出处
期刊:Leukemia
[Springer Nature]
日期:2021-07-29
卷期号:: 1-12
标识
DOI:10.1038/s41375-021-01346-7
摘要
Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes. Here, we find that the RNA-binding protein IGF2BP3, which is overexpressed in MLL-translocated leukemia, strongly amplifies MLL-Af4-mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4-driven leukemia and greatly attenuates disease, with a minimal impact on baseline hematopoiesis. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. At the molecular level, IGF2BP3 regulates a complex posttranscriptional operon governing leukemia cell survival and proliferation. IGF2BP3-targeted mRNA transcripts include important MLL-Af4-induced genes, such as those in the Hoxa locus, and the Ras signaling pathway. Targeting of transcripts by IGF2BP3 regulates both steady-state mRNA levels and, unexpectedly, pre-mRNA splicing. Together, our findings show that IGF2BP3 represents an attractive therapeutic target in this disease, providing important insights into mechanisms of posttranscriptional regulation in leukemia.
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