miR-103 Sensitizes Hemopoietic Tumor Cells for Glucocorticoid Induced Apoptosis

Glucocorticoid (GC) hormones are an important ingredient of leukemia therapy since they are potent inducers of lymphoid cell apoptosis. However, the development of GC resistance remains an obstacle in GC based treatment. In the present investigation we used deep sequencing analysis to detect miRNAs that interplay in the apoptotic response of leukemic cells to GC. The most significantly upregulated miRNA having the strongest influence on GC induced apoptosis (GCIA) was miR-103. Transfection of GC resistant cells with miR-103 sensitized them to GCIA, while miR-103 sponging of GC sensitive cells rendered them partially resistant. miR-103 is encoded within the fifth intron of PANK3 gene. We demonstrate that the GC receptor (GR) upregulates miR-103 by direct interaction with GC response element (GRE) in the PANK3 enhancer. Consequently, miR-103 targets the c-Myc activators c-Myb and DVL1, thereby reducing c-Myc expression. Since c-Myc is a transcription factor of the miR-17∼92a poly-cistron, all six miRNAs of the latter are also downregulated. Of these, miR-18a and miR-20a are involved in GCIA, as they target GR and BIM, respectively. Consequently, GR and BIM expression are elevated, thus advancing GCIA. Furthermore, miR-103 reduces the expression of cycline dependent kinase (CDK2) and its cycline E1 target, as well as cellular proliferation. Altogether, this study highlights miR-103 as a useful prognostic biomarker and drug for leukemia management in the future.