Abstract
Acute myeloid leukemia (AML) is an aggressive and heterogeneous bone marrow malignancy, the only curative treatment being intensive chemotherapy eventually in combination with allogeneic stem cell transplantation. Both the AML and their neighboring stromal cells show constitutive chemokine release, but chemokines seem to function as regulators of AML cell proliferation only for a subset of patients. Chemokine targeting is therefore considered not only for immunosuppression in allotransplanted patients but also as a possible antileukemic strategy in combination with intensive chemotherapy or as part of disease-stabilizing treatment at least for the subset of patients with chemokine-responsive AML cells. In this study, we characterized more in detail the leukemia cell phenotype of the chemokine-responsive patients. We investigated primary AML cells derived from 79 unselected patients. Standardized in vitro suspension cultures were used to investigate AML cell proliferation, and global gene expression profiles were compared for chemokine responders and non-responders identified through the proliferation assays. CCL28-induced growth modulation was used as marker of chemokine responsiveness, and 38 patients were then classified as chemokine-responsive. The effects of exogenous CCL28 (growth inhibition/enhancement/no effect) thus differed among patients and was also dependent on the presence of exogenous hematopoietic growth factors as well as constitutive AML cell cytokine release. The effect of CCR1 inhibition in the presence of chemokine-secreting mesenchymal stem cells also differed among patients. Chemokine-responsive AML cells showed altered expression of genes important for (i) epigenetic transcriptional regulation, particularly lysine acetylation; (ii) helicase activity, especially DExD/H RNA helicases; and (iii) angioregulatory proteins important for integrin binding. Thus, chemokine responsiveness is part of a complex AML cell phenotype with regard to extracellular communication and transcriptional regulation. Chemokine targeting in chemokine-responsive patients may thereby alter AML cell trafficking and increase their susceptibility toward antileukemic treatment, e.g., conventional chemotherapy or targeting of other phenotypic characteristics of the chemokine-responsive cells.
Highlights
Acute myeloid leukemia (AML) is an aggressive disease characterized by infiltration of malignant myeloblasts in the bone marrow; the only curative treatment is intensive chemotherapy potentially in combination with allogeneic stem cell transplantation [1]
We first compared AML cell proliferation for cultures prepared in medium alone and medium supplemented with 20 ng/mL of CCL28 for all 79 patients
Chemokines have growth-modulating effects on the AML cells only for a minority of patients; and these patients are responsive to several chemokines
Summary
Acute myeloid leukemia (AML) is an aggressive disease characterized by infiltration of malignant myeloblasts in the bone marrow; the only curative treatment is intensive chemotherapy potentially in combination with allogeneic stem cell transplantation [1]. In vitro studies suggest that chemokines function as growth regulators in leukemic hematopoiesis only for a subset of AML patients, and a wide range of both CCL and CXCL chemokines can modulate leukemia cell proliferation [4]. One of these chemokines is CCL28 [4] that is released by non-leukemic bone marrow stromal cells, and that preserves the functional integrity of normal hematopoietic progenitor cells [12] through binding to the G-protein-coupled receptors (GPCRs) CCR3 and CCR10 [13,14,15]. CCR3 is a promiscuous receptor, which can bind several ligands in addition to CCL28, whereas CCR10 can only bind CCL27 and CCL28 [16]
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