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

  • Author(s): Tran, Tiffany M
  • Philipp, Julia
  • Bassi, Jaspal Singh
  • Nibber, Neha
  • Draper, Jolene M
  • Lin, Tasha L
  • Palanichamy, Jayanth Kumar
  • Jaiswal, Amit Kumar
  • Silva, Oscar
  • Paing, May
  • King, Jennifer
  • Katzman, Sol
  • Sanford, Jeremy R
  • Rao, Dinesh S
  • et al.

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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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