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RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation
Jayanth Kumar Palanichamy, … , Jeremy R. Sanford, Dinesh S. Rao
Jayanth Kumar Palanichamy, … , Jeremy R. Sanford, Dinesh S. Rao
Published March 14, 2016
Citation Information: J Clin Invest. 2016;126(4):1495-1511. https://doi.org/10.1172/JCI80046.
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Research Article Hematology

RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation

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Abstract

Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia–rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3′ untranslated regions (3′UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.

Authors

Jayanth Kumar Palanichamy, Tiffany M. Tran, Jonathan M. Howard, Jorge R. Contreras, Thilini R. Fernando, Timothy Sterne-Weiler, Sol Katzman, Masoud Toloue, Weihong Yan, Giuseppe Basso, Martina Pigazzi, Jeremy R. Sanford, Dinesh S. Rao

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Figure 9

Expression of IGF2BP3 RNA-binding domain mutants in vivo and in vitro.

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Expression of IGF2BP3 RNA-binding domain mutants in vivo and in vitro.
(...
(A) Schematic of IGF2BP3 with its binding domains and the respective mutants (KH and RRM). (B) Time course of normalized engraftment to MIG in PB between 4 and 20 weeks after transplant. (C) FACS of PB done at 4 weeks after BMT, showing CD45.2 and GFP positivity (one-way ANOVA followed by Bonferroni’s test; ***P < 0.001). (D) B cells in PB 16 weeks after transplant. (E) Myeloid cells in PB 12 weeks after transplant. n = 8 for all groups. Mutant BMT experiment was completed twice for validation. (F) Western blot confirmed expression of IGF2BP3 (64 kDa), KH (47 kDa), and RRM (22 kDa) proteins in 7OZ/3 using anti-T7 (top panel) and anti-IGF2BP3 (bottom) antibodies. Actin used as a loading control. (G) Luciferase assay shows increased luciferase activity for the MYC 3′UTR when cotransfected with hI3 and decreased luciferase activity for the MYC 3′UTR when cotransfected with KH and RRM mutants (t test hI3, K,H and RRM; ***P < 0.001; ****P < 0.0001). Experiment was completed 3×. Data represent mean ±SD. hI3, human IGF2BP3; PB, peripheral blood.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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