BBB seminar: Øystein Bruserud
The chemokine system in acute myelogenous leukemia
Section of Haematology, Institute of Medicine, University of Bergen
Acute myelogenous leukemia (AML) is an aggressive disorder characterized by bone marrow accumulation of immature leukemia cells. The biological phenotype of the malignant cells shows a wide variation between different AML patients, but a fundamental characteristic of these malignant cells is their constitutive release of a wide range of soluble mediators, including several CCL and CXCL chemokines involved in angiogenesis, growth control and immunomodulation. Firstly, primary AML cells usually show a broad chemokine release profile, and based on correlation analysis of chemokine release the following three chemokine clusters could be identified: CCL2-4/CXCL1/8 (all chemokines usually released at high levels), CCL5/CXCL9-11 and CCL13/17/22/24/CXCL5/6. Only the CCL2-4/CXCL1/8 cluster seems to involve a common regulation at the mRNA level as these chemokine protein levels correlate with NF k B expression. Secondly, the constitutive chemokine release may be important for the increased bone marrow angiogenesis observed in AML patients. Proangiogenic CXCL8 is the chemokine that is released at highest levels by AML cells, and this release can be further increased by nonleukemic bone marrow stromal cells. The antiangiogenic CXCL4/CXCL9-11 chemokines are usually released at lower levels. Thirdly, the release of chemotactic chemokines may increase the local recruitment of leukemia-reactive T cells to the AML microenvironment and thereby be important for antileukemic immune reactivity, e.g. after allogeneic stem cell transplantation. To conclude, constitutive chemokine release by AML cells is probably important both for leukemogenesis and chemosensitivity in human AML.