Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 4, Pages 1495-1511Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI80046
Keywords
-
Categories
Funding
- NIH [R01 CA166450, R01GM109146, R21AG042003, AI-28697, P30CA016042]
- UCLA JCCC
- Career Development Award [K08CA133521]
- Tumor Immunology Training Grant, NIH [T32CA009120]
- Tumor Biology Training Grant NIH [T32CA009056]
- JCCC
- UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
- [R41HG007336]
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available