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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.
Highlights
Chromosomal rearrangements of the mixed-lineage leukemia (MLL, KMT2A) gene are recurrently found in a subset of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute leukemia of ambiguous lineage [1]
Enforced expression of another MLL fusion protein, MLL-AF9, and other non-MLL leukemia drivers, including AML1-ETO, MYC, and NRAS in primary hematopoietic stem and progenitor cells (HSPC), show that the upregulation of Igf2bp3 is specific to MLL-Af4 (Supplementary Fig. 1f)
We found that a significant fraction of the differentially expressed mRNAs are bound by IGF2BP3 (Supplementary Fig. 6b)
Summary
Chromosomal rearrangements of the mixed-lineage leukemia (MLL, KMT2A) gene are recurrently found in a subset of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute leukemia of ambiguous lineage [1]. At the posttranscriptional level, emerging evidence suggests a role for microRNAs, RNA-binding proteins (RBP), and other RNAbased mechanisms in regulating gene expression during leukemogenesis [19,20,21]. IGF2BP3 interacted with and upregulated oncogenic transcripts (e.g., MYC, CDK6) via the 3′UTR, contributing to the pathologic proliferative phenotype [22] Together, these studies illuminated a novel role for posttranscriptional gene regulation in the pathologic proliferation of HSPCs. Experimentally, MLL-AF4-driven leukemogenesis has been studied using a range of in vitro and in vivo models leading to significant progress in our understanding of MLL-rearranged leukemia [16, 27,28,29,30,31]. We found that IGF2BP3 targets and modulates the expression of transcripts encoding regulators of leukemogenesis, through multiple posttranscriptional mechanisms. Enrichment analyses were completed with Metascape [44] and gene set enrichment analysis (GSEA) using GSEAPreranked after π-value calculation [45,46,47]
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