The regulation of tumor-suppressive microRNA, miR-126, in chronic lymphocytic leukemia.
Guinn D, Lehman A, Fabian C, Yu L, Maddocks K, Andritsos LA, Jones JA, Flynn JM, Jaglowski SM, Woyach JA, Byrd JC, Johnson AJ
Cancer Med 6 778-787 04/01/2017
The introduction of miR profiling of chronic lymphocytic leukemia (CLL) patients with different cytogenetic profiles and responses to therapy has allowed incorporation of important miR-mRNA interactions into the understanding of disease biology. In this study, we performed miR expression analysis using NanoString nCounter to discover differentially regulated miRs after therapy with the Bruton tyrosine kinase inhibitor ibrutinib. Of the differentially regulated miRs in the discovery set, miR-29c and miR-126 were confirmed using real-time PCR to be upregulated in CLL patient cells with ibrutinib therapy. In the validation set, an inverse correlation was observed between miR-126 levels and expression of its putative target p85ß, an isoform of the phosphoinositide 3-kinase p85 regulatory subunit. We found that mRNA for the host gene EGFL7, primary unprocessed miR-126, and mature miR-126 are all downregulated in CLL cells compared to normal B cells. Patients in later stages of disease have a greater decrease in miR-126 expression compared to treatment-naive patients, indicating that lower miR-126 levels may associate with disease progression. Overexpression of miR-126 in leukemia cell lines significantly downregulates p85ß expression and decreases activation of prosurvival mitogen-activated protein kinase (MAPK) signaling. These results implicate miR-126 in the pathology of CLL.Full Text