The chemokine system and its contribution to leukemogenesis and treatment responsiveness in patients with acute myeloid leukemia

Abstract

The chemokine family consists of approximately 50 small (8-14 kDa), basic proteins that are expressed and released by a wide range of normal and malignant cells. Most chemokines act through heptahelical transmembrane G protein- coupled receptors. Based on their molecular structure these cytokines are divided into the two major subgroups CCL and CXCL chemokines that bind to CCR or CXCR receptors respectively. Primary human acute myelogenous leukemia (AML) cells show constitutive release of a wide range of chemokines, but the chemokine release profile differs between patients. Among the commonly expressed chemokines are proangiogenic CXCL8, antiangiogenic CXCL4/9-11 and several leukocyte-chemotactic chemokines. Systemic serum levels of leukocyte-chemotactic chemokines depend both on patient age, disease status, the chemotherapy regimen and development of complicating infections. The local chemokine network in human AML is probably further modulated by the hypoxic bone marrow microenvironment and the local release of chemokines by nonleukemic bone marrow stromal cells. Usually primary AML cells also express several chemokine receptors. Specific chemokine inhibitors are now being developed, including chemokine-neutralizing or receptor-blocking antibodies, antisense strategies, receptor-blocking small molecules or inhibitors of downstream signaling. The use of CXCR4-antagonists for mobilization of peripheral blood stem cells has been documented in several clinical studies. Although animal studies suggest that chemokine inhibition also may become useful in the treatment of graft versus host disease, the possible use of chemokine-targeting therapy for other indications than stem cell mobilization requires further studies.