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Acute Leukemias

MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia

Leukemia volume 29, pages 798–806 (2015)Cite this article

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Abstract

The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3′untranslated region–microRNA (miRNA) library screen and identified 33 putative MYB-targeting miRNAs. Subsequently, transcriptome data from two independent T-ALL cohorts and different subsets of normal T-cells were used to select miRNAs with relevance in the context of normal and malignant T-cell transformation. Hereby, miR-193b-3p was identified as a novel bona fide tumor-suppressor miRNA that targets MYB during malignant T-cell transformation thereby offering an entry point for efficient MYB targeting-oriented therapies for human T-ALL.

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Acknowledgements

We thank the members of the Wendel lab and the members of the Speleman lab for experimental support and discussions during this research project and Aline Eggermont for excellent technical assistance. Furthermore, we also thank The Memorial Sloan Kettering (MSK) animal facility and Research Animal Resource Center (RARC) for assistance with mouse experiments. This work is supported by: the Fund for Scientific Research Flanders (FWO) (research projects G.0202.09 and G.0869.10N to FS, 3GA00113N to PVV and G0B2913N and G037514N to TT, research grant 1.5.210.11N to PR; PhD grant to JVdM; postdoctoral grants to TT, PM, PVV, SG, IVdW and PR; BP is a senior clinical investigator), the Belgian Foundation against Cancer (to FS, JV (SCIE 2010-177) and SG), the Flemish Liga against Cancer (VLK) (PhD grant to JVdM and GVP); Ghent University (GOA grant 12051203 to FS; BOF10/PDO/140 to PR; BOF01D35609 to GVP), the Cancer Plan from the Federal Public Service of Health (to FS), the Children Cancer Fund Ghent (to FS) and the Belgian Program of Interuniversity Poles of Attraction (365O9110 to FS, project grant 2010-187 to TL). Additional funding was provided by the NCI (R01-CA142798-01 and U01CA105492-08), the Leukemia Research Foundation, the Experimental Therapeutics Center at MSKCC, the American Cancer Society and the Geoffrey Beene Cancer Center (all to H-GW). This work was further supported by the Cancéropôle d’Ile de France (IDF), the program Carte d’Identité des Tumeurs (CIT) from the Ligue Nationale contre le Cancer, ERC St Grant Consolidator 311660) and the ANR-10-IBHU-0002 Saint-Louis Institute program (all to JS).

Author Contributions

EM and JVdM performed the laboratory experiments and data analysis; GVP, PM, PR and MB assisted with experiments and data-mining. GVP, PM and JV designed the high-throughput 3′UTR–miRNA library screens. JVdM, MB and H-GW performed and coordinated the mouse experiments. TT, IVdW, YB, BDM, NVR, BP, JS and EC collected and analyzed diagnostic T-ALL and normal thymocyte samples. EM, JVdM, PVV, FS and PR designed the experiments, coordinated the research and wrote the paper.

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Author notes

  1. E Mets and J Van der Meulen: These two authors shared co-authorship.

Authors and Affiliations

  1. Center for Medical Genetics, Ghent University, Ghent, Belgium

    E Mets, J Van der Meulen, G Van Peer, P Mestdagh, N Van Roy, B Poppe, J Vandesompele, P Rondou, P Van Vlierberghe & F Speleman

  2. Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M Boice & H-G Wendel

  3. Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium

    I Van de Walle & T Taghon

  4. Department of Pediatric Hematology—Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

    T Lammens, B De Moerloose & Y Benoit

  5. VIB/Department for Molecular Biomedical Research, Ghent University, Ghent, Belgium

    S Goossens

  6. Genome Rearrangements and Cancer Laboratory, U462 INSERM, Laboratoire Central d’Hématologie and Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France

    E Clappier & J Soulier

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  1. E Mets
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Correspondence to F Speleman.

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Mets, E., Van der Meulen, J., Van Peer, G. et al. MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia. Leukemia 29, 798–806 (2015). https://doi.org/10.1038/leu.2014.276

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