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

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 7

Cross-validation of IGF2BP3 iCLIP targets with IGF2BP3-sensitive differentially expressed genes.

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Cross-validation of IGF2BP3 iCLIP targets with IGF2BP3-sensitive differe...
(A) Volcano plot of differentially expressed genes (blue dots) determined using DESeq analysis on RNA-Seq samples from control and IGF2BP3 knockdown RS4;11 cells (as described in Figure 2). Differentially expressed genes identified as IGF2BP3 targets by iCLIP are highlighted (orange dots). Dots demarcated by black outlines are leukemogenic genes by GO analysis of OMIM-associated disease pathways. Dotted lines represent 1.5-fold–change in expression (vertical lines) and P < 0.05 cutoff (horizontal line). (B and C) GO analysis of gene subgroups showing increased expression (B) and decreased expression (C) with IGF2BP3 knockdown using ENRICHR gene list enrichment analysis webtool. Term lists used in this analysis were GO_Biological_Processes and KEGG to determine enriched processes and pathways from our cross-validated list of 269 IGF2BP3-targeted and -sensitive genes. Vertical dotted lines represent P value cutoff (P < 0.05). KD, knockdown.