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 (MLLrearranged) 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 diseas

Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

“…In control experiments, treatment of adult progenitors with BET inhibitors failed to upregulate the cytoskeletal remodeling factors or HEXIM1, failed to induce RNAPII hyperphosphorylation, and did not induce cellular enlargement (Supplemental Figure 11, C-E). During the preparation of this manuscript, Palanichamy et al also showed repression of IGF2BP3 expression by BET inhibition (36).…”

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

“…Although IMP1 and IMP3 may also bind to MREs or in their immediate vicinity, safe-housing transcripts in a RISC-free environment constituted of mRNP granules is currently the best-understood mechanism by which they protect their target mRNAs. lymphoid-primed multipotent progenitors (LMPPs), and common lymphoid progenitors (CLPs) in the bone marrow, with increased proliferation of HSCs and LMPPs (Palanichamy et al 2016). Mouse hematopoiesis was skewed toward the myeloid and B-cell lineages accompanied by leukocytosis in the peripheral blood, atypical infiltration of B cells into the thymic medulla, and increased myeloid cell numbers in the spleen (Palanichamy et al 2016).…”

“…lymphoid-primed multipotent progenitors (LMPPs), and common lymphoid progenitors (CLPs) in the bone marrow, with increased proliferation of HSCs and LMPPs (Palanichamy et al 2016). Mouse hematopoiesis was skewed toward the myeloid and B-cell lineages accompanied by leukocytosis in the peripheral blood, atypical infiltration of B cells into the thymic medulla, and increased myeloid cell numbers in the spleen (Palanichamy et al 2016). The observed phenotype was ascribed to stabilization of Myc and Cdk6 mRNAs by IMP3 based on individual nucleotide-resolution CLIP (iCLIP) analysis and reporter assays.…”

“…The observed phenotype was ascribed to stabilization of Myc and Cdk6 mRNAs by IMP3 based on individual nucleotide-resolution CLIP (iCLIP) analysis and reporter assays. However, the mechanism of the stabilization remains to be elucidated, as deletion of single IMP3-binding sites in the 3 ′ UTRs of Myc and Cdk6 failed to reverse the phenotype of the reporter assays (Palanichamy et al 2016).…”

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

“…Furthermore, Igf2bp3 is an important member of a critical upstream signalling pathway that drives cell proliferation (Ennajdaoui et al, 2016;Lederer et al, 2014, Chernoff, 1999. In particular, Igf2bp3 (Palanichamy et al, 2016;Schaeffer et al, 2010) and Ube2c (Bajaj et al, 2016;Chou et al, 2014;Shen et al, 2013;Shuliang et al, 2013) have been widely studied in various cancers, confirming their ability to promote cell proliferation. Interestingly, their expression levels are substantially down-regulated during postnatal cardiac development.…”