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Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells

From the Division for Hematology, Department of Medicine, Haukeland University Hospital and The University of Bergen, Bergen, Norway (OB, AR, AMartO, BTG); Department of Informatics, The University of Bergen, Norway (LS); The Gade Institute, Haukeland University Hospital and The University of Bergen, Norway (AMargO, KHK).

Correspondence: Øystein Bruserud, Medical Department, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail: oystein.bruserud{at}haukeland.no

Background and Objectives: 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.

Design and 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 NFB levels/activation. The chemotaxis of normal immunocompetent cells for patients without constitutive chemokine release was observed to be decreased.

Interpretation and 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.

Key words: acute myelogenous, leukemia, chemokine, NFKB, CXCR2.