Molecular targets for therapy

RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1

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Abstract

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an oncofetal protein expressed in various cancers including leukemia. In this study, we assessed the role of IGF2BP1 in orchestrating leukemia stem cell properties. Tumor-initiating potential, sensitivity to chemotherapeutic agents, and expression of cancer stem cell markers were assessed in a panel of myeloid, B-, and T-cell leukemia cell lines using gain- and loss-of-function systems, cross-linking immunoprecipitation (CLIP), and photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP) techniques. Here, we report that genetic or chemical inhibition of IGF2BP1 decreases leukemia cells’ tumorigenicity, promotes myeloid differentiation, increases leukemia cell death, and sensitizes leukemia cells to chemotherapeutic drugs. IGF2BP1 affects proliferation and tumorigenic potential of leukemia cells through critical regulators of self-renewal HOXB4 and MYB and through regulation of expression of the aldehyde dehydrogenase, ALDH1A1. Our data indicate that IGF2BP1 maintains leukemia stem cell properties by regulating multiple pathways of stemness through transcriptional and metabolic factors.

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Data availability

Data used for bioinformatics analysis were deposited in NCBI Gene Expression Omnibus (GEO) repository and can be accessed through the series accession numbers GSE138704 and GSE138063.

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Acknowledgements

This study was supported by the NIH grant R01 AR063361 (VSS), NIH Intramural Research Program of the NIAID (SAM), and NIAMS (MH). The authors thankful to Drs Chunhua Song and Joel Yisraeli for the gift of reagents. We also thankful to Yuka Imamura and Penn State Cancer Institute Genomics Sciences, Joe Bednarczyk and Flow Cytometry Core for help with data acquisition and analysis. We thank Gustavo Gutierrez-Cruz and Stefania Dell’Orso (NIAMS) for sequencing the PAR-CLIP libraries, and NIAID Office of Cyber Infrastructure and Computational Biology for high-performance computing.

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Correspondence to Irina A. Elcheva or Vladimir S. Spiegelman.

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Elcheva, I.A., Wood, T., Chiarolanzio, K. et al. RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1. Leukemia (2019) doi:10.1038/s41375-019-0656-9

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