Scherr, M., Elder, A., Battmer, K., Barzan, D., Bomken, S., Ricke-Hoch, M., Schroeder, A., Venturini, L., Blair, H. J., Vormoor, J., Ottmann, Oliver ![]() |
Preview |
PDF
- Published Version
Available under License Creative Commons Attribution. Download (3MB) | Preview |
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: | 04 May 2023 20:24 |
URI: | https://orca.cardiff.ac.uk/id/eprint/96800 |
Citation Data
Cited 46 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
![]() |
Edit Item |