title: 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.
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.
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.|Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.|Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Reikvam
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.|Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Hanne
authors.initials: H
authors.lastname: Fredly
authors.affiliation: Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Jørn
authors.initials: J
authors.lastname: Skavland
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.
authors.forename: Karen-Marie
authors.initials: KM
authors.lastname: Hagen
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.
authors.forename: Tuyen Thy
authors.initials: TT
authors.lastname: van Hoang
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Brenner
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Amir
authors.initials: A
authors.lastname: Kadi
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Astori
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.|Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen, Norway.|Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Pendino
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D061251:Primary Cell Culture; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C540448:CXXC5 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors