Unknown

Dataset Information

0

The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis.


ABSTRACT: 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.

SUBMITTER: Tran TM 

PROVIDER: S-EPMC8727287 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

2021-08-11 | GSE156115 | GEO
| PRJNA656801 | ENA
| S-EPMC8387021 | biostudies-literature
| S-EPMC8282044 | biostudies-literature
| S-EPMC3011030 | biostudies-literature
| S-EPMC5058691 | biostudies-literature
| S-EPMC5341809 | biostudies-literature
| S-EPMC3128482 | biostudies-literature
| S-EPMC6798510 | biostudies-literature
| S-EPMC4811152 | biostudies-literature