MYC-dependent recruitment of RUNX1 and GATA2 on the SET oncogene promoter enhances PP2A inactivation in acute myeloid leukemia

// Raffaella Pippa 1 , Ana Dominguez 1 , Raquel Malumbres 1 , Akinori Endo 2 , Elena Arriazu 1, 3 , Nerea Marcotegui 1, 3 , Elizabeth Guruceaga 1 and María D. Odero 1, 3, 4 1 Hematology/Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain 2 Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, UK 3 Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain 4 Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain Correspondence to: María D. Odero, email: modero@unav.es Raffaella Pippa, email: raffa80@gmail.com Keywords: SET, PP2A, AML, MYC, RUNX1 Received: January 11, 2016 Accepted: May 22, 2016 Published: June 06, 2016 ABSTRACT The SET (I2PP2A) oncoprotein is a potent inhibitor of protein phosphatase 2A (PP2A) that regulates many cell processes and important signaling pathways. Despite the importance of SET overexpression and its prognostic impact in both hematologic and solid tumors, little is known about the mechanisms involved in its transcriptional regulation. In this report, we define the minimal promoter region of the SET gene, and identify a novel multi-protein transcription complex, composed of MYC, SP1, RUNX1 and GATA2, which activates SET expression in AML. The role of MYC is crucial, since it increases the expression of the other three transcription factors of the complex, and supports their recruitment to the promoter of SET . These data shed light on a new regulatory mechanism in cancer, in addition to the already known PP2A-MYC and SET-PP2A. Besides, we show that there is a significant positive correlation between the expression of SET and MYC , RUNX1 , and GATA2 in AML patients, which further endorses our results. Altogether, this study opens new directions for understanding the mechanisms that lead to SET overexpression, and demonstrates that MYC, SP1, RUNX1 and GATA2 are key transcriptional regulators of SET expression in AML.