title: Connexin expression in human acute myeloid leukemia cells: identification of patient subsets based on protein and global gene expression profiles.
abstract: Bone marrow stromal cells support both normal and malignant hematopoiesis. Τhis support is mediated through the local cytokine network and by direct cell‑cell interactions mediated via adhesion molecules and the formation of gap junctions by connexins. Previous studies on connexins in human acute myeloid leukemia (AML) have mainly focused on the investigation of leukemia cell lines. In the present study, we therefore investigated the expression of various connexins at the protein (i.e., cell surface expression) and mRNA level in primary human AML cells. The cell surface expression of the connexins, Cx26, Cx32, Cx37, Cx43 and Cx45, varied considerably between patients, and detectable levels were observed only for subsets of patients. On the whole, Cx43 and Cx45 showed the highest cell surface expression. Connexin expression was dependent on AML cell differentiation, but showed no association with cytogenetic abnormalities or mutations of the fms-related tyrosine kinase 3 (FLT3) or nucleophosmin (NPM)‑1 genes. By contrast, only Cx45 showed a significant variation between patients at the mRNA level. A high Cx45 expression was associated with the altered regulation of the mitogen‑activated protein kinase (MAPK) pathway and the release of pro-inflammatory cytokines [interleukin (IL)‑17, tumor necrosis factor (TNF), interferon‑γ], whereas a low Cx45 expression was associated with the altered regulation of protein functions (i.e., ligase activity, protein folding and catabolism). There was no significant correlation observed between the connexin mRNA and protein levels. Thus, differences in connexin expression can be used to subclassify AML patients. Differences in connexin cell surface expression profiles are not reflected at the mRNA level and have to be directly examined, whereas variations in Cx45 mRNA expression are associated with differences in cell signaling and the regulation of protein functions.
authors.affiliation: Institute of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Reikvam
authors.affiliation: Institute of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Anita
authors.initials: A
authors.lastname: Ryningen
authors.affiliation: Department of Health Studies, University of Stavanger, Stravanger, Norway.
authors.forename: Lars Rune
authors.initials: LR
authors.lastname: Sæterdal
authors.affiliation: Institute of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Ina
authors.initials: I
authors.lastname: Nepstad
authors.affiliation: Department of Health Studies, University of Stavanger, Stravanger, Norway.
authors.forename: Brynjar
authors.initials: B
authors.lastname: Foss
authors.affiliation: Institute of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D015331:Cohort Studies; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D015703:Antigens, CD; D017630:Connexins; C000607042:GJB2 protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000090243:Nucleophosmin; D000072259:Connexin 26; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3