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

作者：Scherr M^*; Elder A; Battmer K; Barzan D; Bomken S; Ricke Hoch M; Schroeder A; Venturini L; Blair H J; Vormoor J; Ottmann O; Ganser A; Pich A; Hilfiker Kleiner D; Heidenreich O; Eder M

来源：Leukemia, 2014, 28(3): 554-565.

DOI：10.1038/leu.2013.361

• BCR-ABL
• BCL2
• acute lymphoblastic leukaemia
• miRNA-17-92

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 similar to 92, is regulated by BCR-ABL fusion in chronic myeloid leukaemia, we investigated its role in BCR-ABL translocated ALL. miR-17 similar to 92-encoded miRNAs were significantly less abundant in BCR-ABL-positive as compared to-negative ALL-cells and overexpression of miR-17 similar to 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 similar to 19b. We validated Bcl2 as a direct target of this miRNA cluster in mice and humans, and, similar to miR-17 similar to 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 similar to 92 in regulation of apoptosis, and identify BCL2 as a therapeutic target of particular relevance in BCR-ABL-positive ALL.

• 出版日期2014-3