MicroRNAs Mediate Resistance to Tyrosine Kinase Inhibitors in Philadelphia-Positive B-ALL by Down-Regulating Key Tumor Suppressors

Abstract 2553

The Philadelphia (Ph) chromosome (t(9;22)(q34;q11)) is the most common recurrent cytogenetic abnormality in adult B-cell acute lymphoblastic leukemia (B-ALL). Resulting expression of the BCR-ABL fusion gene product, a constitutively active tyrosine kinase, leads to an extremely poor prognosis when the disease is treated with chemotherapy alone. In recent years targeted therapy with tyrosine kinase inhibitors (TKIs) in combination with chemotherapy has improved outcomes. Therapeutic resistance remains a major clinical problem, however, with less than half of patients surviving three years from initial therapy in most series even with up-front TKI-chemotherapy regimens. TKI resistance in B-ALL may result from acquired mutations of the BRC-ABL protein or from BCR-ABL-independent causes, including feedback activation of BCL6 or activation of other oncogenic signaling pathways through poorly understood mechanisms. In this study, we screened a whole-genome library of microRNAs for ability to produce resistance to TKI therapy in murine pro-B cells transformed with BCR-ABL. Several initial candidates from the screen were individually confirmed to confer TKI resistance, including miR 148/152 and 19, known oncomirs in T-ALL. Computational analysis of the gene targets of validated miRs shows significant overlap at several tumor-suppressor pathways, including down-regulation of PTEN, a known mechanism of TKI resistance in Ph+ B-ALL cell lines. In sum, we have identified a novel mechanism of TKI resistance in Ph+ B-ALL mediated by miRs and leading to down-regulation of specific tumor suppressive intermediates. These findings will allow development of new therapeutic combinations to improve outcomes for B-ALL patients.