Similarly, neither age nor white blood cell count was correlated with TKI response by a Mann-Whitney test (supplemental Tables 9-10). potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL1 may provide a valuable strategy for overcoming drug resistance in patients. Visual Abstract Open in a separate window Introduction One of the greatest barriers to treating cancer is drug resistance.1 In leukemia, this is primarily because of the inability of available therapeutics to eradicate a unique subset of persisting drug-resistant cells, with stem cell properties and the unique ability to regenerate disease recurrence.2,3 Imatinib mesylate (IM) and other BCR-ABL1 tyrosine kinase inhibitors (TKIs) are among the first examples of highly effective therapeutics that specifically target the kinase Emiglitate activity encoded in the fusion gene in patients with early-phase chronic myeloid leukemia (CML).4-7 However, TKI monotherapies are generally not curative, as most patients harbor residual leukemic stem cells (LSCs), and disease usually recurs if TKI therapy is discontinued.8,9 In fact, LSCs (and their progenitors) are relatively insensitive to TKIs and are genetically unstable, enabling aggressive subclones to emerge over time.3,10-12 Treatment of resistant chronic or accelerated phase CML, blast crisis CML, and BCR-ABL1+ acute lymphoblastic leukemia (ALL), which closely resembles the lymphoid blast crisis of CML, pose even greater challenges, Rabbit Polyclonal to hCG beta as TKI monotherapy is less effective.13-16 Allogeneic transplants remain the only curative therapy, but the associated risk for mortality and morbidity, restrictions to younger patients, and a lack of suitable donors limit their utility.17 Therefore, predictive biomarkers and novel therapeutic methods are clearly needed. The discovery of microRNAs (miRNAs) and their role in regulating normal physiological processes and in the pathogenesis of human cancers has been a revolutionary development.18 miRNAs are small, noncoding, single-stranded RNAs of 18 to 25 nucleotides that control gene expression by destabilizing target transcripts and inhibiting their translation.18 They play a key role in regulating multiple biological processes, including cell proliferation, survival, and differentiation in many tissues, including the process of hematopoietic cell production.19-21 Aberrantly expressed miRNAs that act as tumor promoters or suppressors have been implicated in many diseases, including cancer.22,23 The ability of miRNAs to target Emiglitate multiple genes and signaling pathways has also created immense interest in their power as predictive and diagnostic biomarkers, and as innovative therapeutic agents.24,25 In human acute myeloid leukemia, miRNAs have already been recognized and found to correlate with risk categories and progression.24,26-28 In CML, miRNA expression profiling or target gene predictions have been used to identify miRNAs that Emiglitate directly target was uncovered as a target gene of miR-185, with inversely correlated expression, mediating drug resistance in TKI nonresponder cells. Further studies provided new insights into how this information might predict patient responses to therapy and improve the treatment of CML and BCR-ABL1+ ALL. Methods Human cells Heparin-anticoagulated peripheral blood (PB) or bone marrow (BM) cells were obtained from 22 (cohort 1) or 58 (cohort 2) newly diagnosed patients with CML-chronic phase at diagnosis, before initiation of IM or nilotinib (NL) therapies (supplemental Table 1, available on the Web site; CAMN107E2401-ENESTxtnd phase IIIb clinical trial, ClinicalTrials.gov identifier: “type”:”clinical-trial”,”attrs”:”text”:”NCT01254188″,”term_id”:”NCT01254188″NCT01254188).33 Patients were later classified as TKI responders or nonresponders according to the European Leukemia Net treatment guidelines.34-36 Additional samples were obtained 1 and 3 months posttreatment in the second cohort (116 samples). Normal BM (NBM).