title: 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.forename: Jayanth Kumar
authors.initials: JK
authors.lastname: Palanichamy
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Tran
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Howard
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Contreras
authors.forename: Thilini R
authors.initials: TR
authors.lastname: Fernando
authors.forename: Timothy
authors.initials: T
authors.lastname: Sterne-Weiler
authors.forename: Sol
authors.initials: S
authors.lastname: Katzman
authors.forename: Masoud
authors.initials: M
authors.lastname: Toloue
authors.forename: Weihong
authors.initials: W
authors.lastname: Yan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Martina
authors.initials: M
authors.lastname: Pigazzi
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Sanford
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Rao
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; C495911:CDK6 protein, human; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6