IGF2BP3 remodels the microRNA targeting landscape in MLL-AF4 leukemia
Kabbani, L. E.; Kapoor, S.; Sharma, G. E.; Gutierrez, M.; Neeb, Z. T.; Jaiswal, A.; Ritter, A. J.; Katzman, S.; Feldman, J. E.; Rao, D. S.; Sanford, J. S.
Show abstract
Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3/I3) is a multi-domain RNA-binding protein required for MLL-AF4-driven leukemogenesis, but its mechanism of action remains enigmatic. We hypothesized from our previous work that I3 amplifies oncogenic gene expression by modulating RNA induced silencing complex (RISC) mRNA interactions. To test this, we performed miR-eCLIP of AGO2, the catalytic RISC subunit, in I3 knock-out (I3KO) as well as control B-cell acute lymphoblastic cell lines (B-ALL) and identified I3-dependent AGO2 binding sites on 111 3'UTRs. Analyzing chimeric miRNA-mRNA reads, we observed differential miRNA occupancy in the I3KO compared to control, including increased targeting by miR-181a, a regulator of leukocyte differentiation. Notably, miR-181a overexpression phenocopied I3 loss, implicating I3 in restricting miR-181a-mediated repression. Biochemical assays confirmed direct competition between I3 and AGO2-miRNA complexes for 3'-UTR binding. Taken together, our results provide a model for how I3 promotes leukemogenesis by antagonizing RISC-mediated repression of oncogenic mRNAs.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Cytoplasmic Switch of ARS2 Isoforms Promotes Nonsense-Mediated mRNA Decay and Arsenic Sensitivity 96%
- A high-resolution map of functional miR-181 response elements in the thymus reveals the role of coding sequence targeting and an alternative seed match 96%
- Deep and accurate detection of m6A RNA modifications using miCLIP2 and m6Aboost machine learning 96%
Similar papers in this journal
- 3D genome organization during TGFB-induced transcription requires nuclear microRNA and G-quadruplexes 97%
- The pan-cancer lncRNA PLANE regulates an alternative splicing program to promote cancer pathogenesis 96%
- A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division 96%
Similar papers in this journal
- Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair 95%
- Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2) 94%
- Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma 94%
Similar papers in this journal
- Metabolic regulation of RNA methylation by the m6A-reader IGF2BP3 96%
- 53BP1 interacts with the RNA primer from Okazaki fragments to support their processing during unperturbed DNA replication 95%
- Functional specialization of MITF, TFEB and TFE3 drives radically distinct adaptive gene expression programs in melanoma. 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.