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

  • 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.

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Author:Michaela Scherr, Alex Elder, Karin Battmer, David Barzan, Simon Bomken, Melanie Ricke-Hoch, Anke Schröder, Letizia Venturini, Helen J. Blair, Josef Vormoor, Oliver G. OttmannORCiDGND, Arnold Ganser, Andreas Pich, Denise Hilfiker-Kleiner, Olaf Torben HeidenreichORCiDGND, Matthias Eder
URN:urn:nbn:de:hebis:30:3-300090
DOI:https://doi.org/10.1038/leu.2013.361
ISSN:1476-5551
ISSN:0887-6924
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/24280866
Parent Title (English):Leukemia
Publisher:Nature Publ. Group
Place of publication:Basingstoke
Document Type:Article
Language:English
Year of Completion:2014
Date of first Publication:2013/11/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/05/06
Tag:BCL2; BCR-ABL; acute lymphoblastic leukaemia; miRNA-17–92
Volume:28.2014
Issue:3
Page Number:12
First Page:554
Last Page:565
Note:
Copyright © 2014 Macmillan Publishers Limited This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/
HeBIS-PPN:364477393
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0