title: Functional characteristics and gene expression profiles of primary acute myeloid leukaemia cells identify patient subgroups that differ in susceptibility to histone deacetylase inhibitors.
abstract: Modulation of gene expression through histone deacetylase (HDAC) inhibition is considered a possible therapeutic strategy in acute myeloid leukaemia (AML). In vitro effects and basal gene expression of structurally different HDAC inhibitors were examined. Primary human AML cells were derived from 59 consecutive patients. The HDAC inhibitors valproic acid, PXD101, trichostatin A and sodium butyrate inhibited leukaemic and clonogenic cell proliferation and increased apoptosis in a dose-dependent manner when tested at high concentrations. However, at lower concentrations proliferation increased for a subset of patients. This divergence was also observed in the presence of all-trans retinoic acid, theophylline and decitabine, and in cocultures with bone marrow stromal cells. Levels of IL-1beta, IL-6, GM-CSF and TNFalpha increased. Based on the basal expression of 100 genes the patients with growth enhancement at intermediate HDAC inhibitor concentrations and those without this response were clustered into two mutually exclusive groups. Functional characterization and gene expression analyses identify AML patient subsets that differ in their response to HDAC inhibitors. These observations may explain why HDAC inhibitor therapy affects only a subset of patients.
authors.affiliation: Institute of Medicine, University of Bergen/Haukeland University Hospital, N-5021, Bergen, Norway. camilla.ingvaldsen.stapnes@helse-bergen.no
authors.forename: Camilla
authors.initials: C
authors.lastname: Stapnes
authors.forename: Anita
authors.initials: A
authors.lastname: Ryningen
authors.forename: Kimberley
authors.initials: K
authors.lastname: Hatfield
authors.forename: Anne Margrete
authors.initials: AM
authors.lastname: Øyan
authors.forename: Geir Egil
authors.initials: GE
authors.lastname: Eide
authors.forename: Matthias
authors.initials: M
authors.lastname: Corbascio
authors.forename: Karl-Henning
authors.initials: KH
authors.lastname: Kalland
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017154:Stromal Cells / Q000502:physiology; D013449:Sulfonamides; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C012589:trichostatin A; D014635:Valproic Acid; C487081:belinostat