Expression of the potential therapeutic target CXXC5 in primary acute myeloid leukemia cells - high expression is associated with adverse prognosis as well as altered intracellular signaling and transcriptional regulation

// Øystein Bruserud 1,2 , Håkon Reikvam 1,2 , Hanne Fredly 1,2 , Jørn Skavland 2 , Karen-Marie Hagen 1 , Tuyen Thy van Hoang 1 , Annette K. Brenner 1 , Amir Kadi 4,5,6 , Audrey Astori 4,5,6 , Bjørn Tore Gjertsen 1,2 and Frederic Pendino 3,4,5,6 1 Section for Hematology, Department of Clinical Science, University of Bergen, Norway 2 Department of Medicine, Haukeland University Hospital, Bergen, Norway 3 Department of Molecular Biology, University of Bergen, Bergen, Norway 4 Inserm, U1016, Institut Cochin, F-75014, Paris, France 5 CNRS, UMR8104, F-75014, Paris, France 6 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Correspondence: Øystein Bruserud, email: // Keywords : Acute myeloid leukemia, CXXC5, transcription, cytokines, all-trans retinoic acid Received : April 20, 2014 Accepted : December 21, 2014 Published : December 26, 2014 Abstract The CXXC5 gene encodes a transcriptional activator with a zinc-finger domain, and high expression in human acute myeloid leukemia (AML) cells is associated with adverse prognosis. We now characterized the biological context of CXXC5 expression in primary human AML cells. The global gene expression profile of AML cells derived from 48 consecutive patients was analyzed; cells with high and low CXXC5 expression then showed major differences with regard to extracellular communication and intracellular signaling. We observed significant differences in the phosphorylation status of several intracellular signaling mediators (CREB, PDK1, SRC, STAT1, p38, STAT3, rpS6) that are important for PI3K-Akt-mTOR signaling and/or transcriptional regulation. High CXXC5 expression was also associated with high mRNA expression of several stem cell-associated transcriptional regulators, the strongest associations being with WT1, GATA2, RUNX1, LYL1, DNMT3, SPI1, and MYB. Finally, CXXC5 knockdown in human AML cell lines caused significantly increased expression of the potential tumor suppressor gene TSC22 and genes encoding the growth factor receptor KIT, the cytokine Angiopoietin 1 and the selenium-containing glycoprotein Selenoprotein P. Thus, high CXXC5 expression seems to affect several steps in human leukemogenesis, including intracellular events as well as extracellular communication.