This work unraveled three mRNA/miRNA networks (miR-29a-3p/TET2, miR-660-5p/EPAS1 and miR-494-3p/c-MYC) capable of affecting TKI-sensitivity in CML cells, thus leading to the design of novel targeted therapies aimed at eliminating TKI-resistant LSCs. This evidence concerns the gene EPAS1 and chronic myelogenous leukemia, BCR-ABL1 positive.