Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells.
OBJECTIVE
Chemokines are soluble mediators involved in angiogenesis, cellular growth control and immunomodulation. In the present study we investigated the effects of various chemokines on proliferation of acute myelogenous leukemia (AML) cells and constitutive chemokine release by primary AML cells.


METHODS
Native human AML cells derived from 68 consecutive patients were cultured in vitro. We investigated AML cell proliferation (3H-thymidine incorporation, colony formation), chemokine receptor expression, constitutive chemokine release and chemotaxis of normal peripheral blood mononuclear cells.


RESULTS
Exogenous chemokines usually did not have any effect on AML blast proliferation in the absence of hematopoietic growth factors, but when investigating growth factor-dependent (interleukin 3 + granulocyte-macrophage colony-stimulating factor + stem cell factor) proliferation in suspension cultures the following patient subsets were identified: (i) patients whose cells showed chemokine-induced growth enhancement (8 patients); (ii) divergent effects on proliferation (15 patients); and (iii) no effect (most patients). These patient subsets did not differ in chemokine receptor expression, but, compared to CD34- AML cells, CD34+ cells showed higher expression of several receptors. Chemokines also increased the proliferation of clonogenic AML cells from the first subset of patients. Furthermore, a broad constitutive chemokine release profile was detected for most patients, and the following chemokine clusters could be identified: CCL2-4/CXCL1/8, CCL5/CXCL9-11 (possibly also CCL23) and CCL13/17/22/24/CXCL5 (possibly also CXCL6). Only the CCL2-4/CXCL1/8 cluster showed significant correlations between corresponding mRNA levels and NFkB levels/activation. The chemotaxis of normal immunocompetent cells for patients without constitutive chemokine release was observed to be decreased.


CONCLUSIONS
Differences in chemokine responsiveness as well as chemokine release contribute to patient heterogeneity in AML. Patients with AML can be classified into distinct subsets according to their chemokine responsiveness and chemokine release profile.
Bruserud
Øystein
Ø
Division for Hematology, Department of Medicine, Haukeland University Hospital and The University of Bergen, Bergen, Norway. oystein.bruserud@haukeland.no
Ryningen
Anita
A
Olsnes
Astrid Marta
AM
Stordrange
Laila
L
Øyan
Anne Margrete
AM
Kalland
Karl Henning
KH
Gjertsen
Bjørn Tore
BT
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000145:classification* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D001897:Boronic Acids; D018925:Chemokines; D016298:Hematopoietic Cell Growth Factors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011719:Pyrazines; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D000069286:Bortezomib