Functional characteristics and gene expression profiles of primary acute myeloid leukaemia cells identify patient subgroups that differ in susceptibility to histone deacetylase inhibitors.
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.
Stapnes
Camilla
C
Institute of Medicine, University of Bergen/Haukeland University Hospital, N-5021, Bergen, Norway. camilla.ingvaldsen.stapnes@helse-bergen.no
Ryningen
Anita
A
Hatfield
Kimberley
K
Øyan
Anne Margrete
AM
Eide
Geir Egil
GE
Corbascio
Matthias
M
Kalland
Karl-Henning
KH
Gjertsen
Bjørn Tore
BT
Bruserud
Øystein
Ø
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
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C012589:trichostatin A; D014635:Valproic Acid; C487081:belinostat