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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 4

Analysis of BM progenitor populations from IGF2BP3-overexpressing mice.

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Analysis of BM progenitor populations from IGF2BP3-overexpressing mice.
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(A) Enumeration (left panel) and representative flow cytometry histograms to define HSCs from control vector– (second panel from left), human IGF2BP3– (second from right), and murine IGF2BP3–overexpressing mice (right panel). (B and C) Analysis for LMPPs and CLPs from mice noted as in A. Statistically significant differences were found in LMPPs and CLPs. (D) Intracellular Ki67 staining and FACS-based analyses, depicted in the same manner, with enumeration on the left hand side, within the LSK population enriched for HSCs. Significant differences in the high Ki67-expressing population were found. (E) Intracellular Ki67 staining and FACS analysis of proliferation in the LMPP population shows significant differences in the proliferative fraction. All comparisons used one-way ANOVA followed by Bonferroni’s test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. LSK, Lin–Sca1hic-Kithi. Three separate BMT experiments were completed for validation. Data represent mean ±SD. See also Supplemental Figure 3. hI3, human IGF2BP3; mI3, murine IGF2BP3.

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

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