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Differential expression of miR-17 similar to 92 identifies BCL2 as a therapeutic target in BCR-ABL-positive B-lineage acute lymphoblastic leukemia

Scherr, M., Elder, A., Battmer, K., Barzan, D., Bomken, S., Ricke-Hoch, M., Schroeder, A., Venturini, L., Blair, H. J., Vormoor, J., Ottmann, Oliver, Ganser, A., Pich, A., Hilfiker-Kleiner, D., Heidenreich, O. and Eder, M. 2014. Differential expression of miR-17 similar to 92 identifies BCL2 as a therapeutic target in BCR-ABL-positive B-lineage acute lymphoblastic leukemia. Leukemia 28 (3) , pp. 554-565. 10.1038/leu.2013.361

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Abstract

Despite advances in allogeneic stem cell transplantation, BCR-ABL-positive acute lymphoblastic leukaemia (ALL) remains a high-risk disease, necessitating the development of novel treatment strategies. As the known oncomir, miR-17∼92, is regulated by BCR-ABL fusion in chronic myeloid leukaemia, we investigated its role in BCR-ABL translocated ALL. miR-17∼92-encoded miRNAs were significantly less abundant in BCR-ABL-positive as compared to -negative ALL-cells and overexpression of miR-17∼19b triggered apoptosis in a BCR-ABL-dependent manner. Stable isotope labelling of amino acids in culture (SILAC) followed by liquid chromatography and mass spectroscopy (LC-MS) identified several apoptosis-related proteins including Bcl2 as potential targets of miR-17∼19b. We validated Bcl2 as a direct target of this miRNA cluster in mice and humans, and, similar to miR-17∼19b overexpression, Bcl2-specific RNAi strongly induced apoptosis in BCR-ABL-positive cells. Furthermore, BCR-ABL-positive human ALL cell lines were more sensitive to pharmacological BCL2 inhibition than negative ones. Finally, in a xenograft model using patient-derived leukaemic blasts, real-time, in vivo imaging confirmed pharmacological inhibition of BCL2 as a new therapeutic strategy in BCR-ABL-positive ALL. These data demonstrate the role of miR-17∼92 in regulation of apoptosis, and identify BCL2 as a therapeutic target of particular relevance in BCR-ABL-positive ALL.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Nature Publishing Group
ISSN: 0887-6924
Date of First Compliant Deposit: 15 December 2016
Last Modified: 07 Feb 2019 12:12
URI: http://orca.cf.ac.uk/id/eprint/96800

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