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.
Highlights
Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease with multiple, prognostically relevant genetic aberrations
557 RESULTS miR-17B92 is downregulated in BCR-ABL-positive human ALL samples We previously demonstrated an increased miR-17B92 expression in chronic phase chronic myeloid leukaemia CD34 þ cells, compared to normal CD34 þ cells from healthy donors.[14]
In a search for new therapeutic strategies in BCR-ABL-positive ALL, we identified targets of miRNAs with differential expression and function in these cells
Summary
Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease with multiple, prognostically relevant genetic aberrations. The historically poor outcome of Ph þ ALL patients has been substantially improved by combining tyrosine kinase inhibitors with induction and post-remission chemotherapy, resulting in higher remission rates and a greater proportion of patients undergoing allogeneic hematopoietic stem cell transplantation (SCT).[5,6,7] At present, myeloablative conditioning followed by allogeneic SCT remains the only established curative therapy, with several prospective trials showing an overall survival of 30–65%.8–10.
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