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.