The importance of individual microRNAs (miRNAs) has been established in specific cancers. However, a comprehensive analysis of the contribution of miRNAs to the pathogenesis of any specific cancer is lacking. Here we show that in T-cell acute lymphoblastic leukemia (T-ALL), a small set of miRNAs is responsible for the cooperative suppression of several tumor suppressor genes. Cross-comparison of miRNA expression profiles in human T-ALL with the results of an unbiased miRNA library screen allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) that are capable of promoting T-ALL development in a mouse model and which account for the majority of miRNA expression in human T-ALL. Moreover, these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL, including IKAROS (also known as IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. Thus, a comprehensive and unbiased analysis of miRNA action in T-ALL reveals a striking pattern of miRNA-tumor suppressor gene interactions in this cancer.
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We thank A.J. Capobianco, L. Beverly, A.A. Ferrando, J. Cools and W. Pear for reagents. The Memorial Sloan Kettering (MSK) animal facility and Research Animal Resource Center (RARC), A. Viale of the MSK Genomics Core, H. Zhao of Computational Biology (cBIO) program, K. Huberman of the Geoffrey Beene Translational Oncology Core Facility and J. Schatz for editorial advice. This work is supported by grants from the National Cancer Institute (NCI) (R01-CA142798-01) (H.-G.W.), and a P30 supplemental award (H.-G.W.), the Louis V. Gerstner Foundation (H.-G.W.), the William Lawrence and Blanche Hughes (WLBH) Foundation (H.-G.W.), the Society of MSKCC (H.-G.W.), the Geoffrey Beene Foundation (H.-G.W.), and May & Samuel Rudin Foundation Award (H.-G.W.); W.H. Goodwin and A. Goodwin and the Commonwealth Foundation for Cancer Research, The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center (H.-G.W.), the Fund for Scientific Research (FWO) Flanders (postdoctoral grants to T.T. and P.V.V., PhD grant to J.V.d.M., P.V.V. is a Senior Clinical Investigator of FWO-Vlaanderen, Odysseus program grant to T.T., and project grants G.0198.08 and G.0869.10N to F.S.); the GOA-UGent (grant no. 12051203); Stichting tegen Kanker, FOD ALL the Children Cancer Fund Ghent (F.S.); and the Belgian Program of Interuniversity Poles of Attraction and the Belgian Foundation Against Cancer.
The authors declare no competing financial interests.
Supplementary Figures 1–10 and Supplementary Tables 2–16. (PDF 2785 kb)
miRNA expression in primary T-ALL samples (XLSX 190 kb)
miRNA expression in T-ALL cell lines (XLSX 225 kb)
miRNA expression in normal T-cells and progenitor populations (XLSX 145 kb)
Comparative analysis of miRNA expression between normal T-cells and progenitor populations and human T-ALL samples (XLSX 76 kb)
Computational target prediction (a: by total context score; b: by number of 7- and 8-mer sites) (XLSX 21 kb)
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Mavrakis, K., Van Der Meulen, J., Wolfe, A. et al. A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Nat Genet 43, 673–678 (2011). https://doi.org/10.1038/ng.858
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