Deregulated miRNA expression is known to contribute to cancer development and progression.
Chronic myeloid leukemia (CML) is characterized by the fusion oncogene BCR-ABL encoding the tyrosine kinase BCR-ABL.Imatinib, aselectiveBCR-ABL tyrosinekinase inhibitor (TKI)isthe first line therapy for newly diagnosed CML patients.
We aim to find miRNAs acting as biomarkers in CML pathogenesis and to identify target genes/signaling pathways affected by these miRNAs.
We studied the expression pattern of two BCR-ABL+ cell-lines, K562 and Meg-01 in reference to healthy blood and the expression profile of K562 cells treated with imatinib/dasatinib. According to hierarchical clustering, healthy blood samples were clustered separately from K562 and Meg-01 cells. Untreated K562 cells were clustered separately from treated ones and imatinib & dasatinib treated K562 cells were clustered closely together.
We focused on miRNAs whose expression in K562/Meg-01 cells was opposite to their expression in healthy blood. Seventy-three miRNAs met this criterion. Within these, the expression of 14 miRNAs was routed back to normal levels following TKI treatment. Of these, miRNA-9's expression was high in the CML cell-lines and also in 30% of the tested CML patients. Similarly, miRNA-454's expression was low in the CML cell-lines and also in 30% of the tested CML patients. The expression of both these miRNAs was routed back to normal levels in imatinib treated patients. TargetScan revealed that miR-454 targets genes such as TGFβR1, p21, E2F2, MAPK1, and SMAD4 known to be associated with CML. MiR-9 was found to target ACVR1B, CCNDBP1, SOCS4 and BCL2L11. Our analysis identified CML as the main disease associated with these miRNAs.
We hope that with these preliminary data, we will identify novel deregulated miRNAs and candidate gene targets allowing for a better understanding of the molecular mechanism underlying CML development and propose possible new avenues for therapeutic treatment.
