A tyrosine kinase-STAT5-miR21-PDCD4 regulatory axis in chronic and acute myeloid leukemia cells

// Anne-Sophie Espadinha 1, 2 , Valérie Prouzet-Mauléon 1, 2 , Stéphane Claverol 3 , Valérie Lagarde 1, 2 , Marc Bonneu 3, 4 , François-Xavier Mahon 1, 2 and Bruno Cardinaud 1, 2, 4 1 University of Bordeaux, INSERM U1035, Bordeaux, France 2 University of Bordeaux, INSERM U1218, Bordeaux, France 3 University of Bordeaux, Plateforme Protéome, CGFB, Bordeaux, France 4 Bordeaux Institut National Polytechnique, Bordeaux, France Correspondence to: Bruno Cardinaud, email: bruno.cardinaud@u-bordeaux.fr Keywords: CML, STAT5, miR-21, microRNA, leukemia Received: August 11, 2016      Accepted: June 13, 2017      Published: July 12, 2017 ABSTRACT MicroRNAs (miRNAs) are regulators of several key patho-physiological processes, including cell cycle and apoptosis. Using microarray-based miRNA profiling in K562 cells, a model of chronic myeloid leukemia (CML), we found that the oncoprotein BCR-ABL1 regulates the expression of miR-21, an “onco-microRNA”, found to be overexpressed in several cancers. This effect relies on the presence of two STAT binding sites on the promoter of miR-21, and on the phosphorylation status of STAT5, a transcription factor activated by the kinase activity of BCR-ABL1. Mir-21 regulates the expression of PDCD4 (programmed cell death protein 4), a tumor suppressor identified through a proteomics approach. The phosphoSTAT5 — miR-21 — PDCD4 pathway was active in CML primary CD34 + cells, but also in acute myeloid leukemia (AML) models like MV4.11 and MOLM13, where the constitutively active tyrosine kinase FLT3-ITD plays a similar role to BCR-ABL1 in the K562 cell line.