TY  - JOUR
A1  - Scherr, Michaela
A1  - Elder, Alex
A1  - Battmer, Karin
A1  - Barzan, David
A1  - Bomken, Simon
A1  - Ricke-Hoch, Melanie
A1  - Schröder, Anke
A1  - Venturini, Letizia
A1  - Blair, Helen J.
A1  - Vormoor, Josef
A1  - Ottmann, Oliver G.
A1  - Ganser, Arnold
A1  - Pich, Andreas
A1  - Hilfiker-Kleiner, Denise
A1  - Heidenreich, Olaf Torben
A1  - Eder, Matthias
T1  - Differential expression of miR-17~92 identifies BCL2 as a therapeutic target in BCR-ABL-positive B-lineage acute lymphoblastic leukemia
T2  - Leukemia
N2  - 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.
KW  - BCR-ABL
KW  - BCL2
KW  - acute lymphoblastic leukaemia
KW  - miRNA-17–92
Y1  - 2013
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/30009
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-300090
SN  - 1476-5551
SN  - 0887-6924
N1  - 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/
VL  - 28.2014
IS  - 3
SP  - 554
EP  - 565
PB  - Nature Publ. Group
CY  - Basingstoke
ER  -