Differences in proliferative capacity of primary human acute myelogenous leukaemia cells are associated with altered gene expression profiles and can be used for subclassification of patients.
OBJECTIVE
Proliferative capacity of acute myelogenous leukaemia (AML) blasts is important for leukaemogenesis, and we have investigated whether proliferative capacity of primary human AML cells could be used for subclassification of patients.


METHODS
In vitro proliferative capacity of AML cells derived from two independent groups was investigated. Cells were cultured under highly standardized conditions and proliferation assayed by (3) H-thymidine incorporation after seven days culture. Patients were subclassified by clustering models, and gene expression profile was examined by microarray analyses.


RESULTS
Based on proliferative capacity of the AML cells, three different patient clusters were identified: (i) autocrine proliferation that was increased by exogenous cytokines; (ii) detectable proliferation only in presence of exogenous cytokines; and (iii) low or undetectable proliferation even in presence of exogenous cytokines. Patients with highest proliferative capacity cells had no favourable prognostic impact by NPM-1 mutation. Analysis of gene expression profiles showed that the most proliferative cells generally had altered expression of genes involved in regulation of transcription/RNA functions, whereas patients with high proliferative capacity and internal tandem duplications (ITDs) in the FLT3 cytokine receptor gene had altered expression of several molecules involved in cytoplasmic signal transduction.


CONCLUSIONS
In vitro proliferative capacity of primary human AML cells was considerably variable between patients and could be used to identify biologically distinct patient subsets.
Division for Hematology, Institute of Clinical Science, University of Bergen, Bergen, Norway; Division for Hematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway; Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway.
H
H
Reikvam
A M
AM
Øyan
K H
KH
Kalland
R
R
Hovland
K J
KJ
Hatfield
Ø
Ø
Bruserud
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019898:Autocrine Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D019295:Computational Biology; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D020440:Gene Duplication; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3