![]() (37, 38) previously showed that some human AML cells express CXCR4 and can also migrate toward a gradient of SDF-1 in a transendothelial migration assay in vitro. The VLA-4 mediated adhesion of leukemic cells with stromal layers prevents the apoptosis of leukemic cells, attenuating their chemotherapy-induced cell death and may be crucial in BM minimal residual disease and AML prognosis (35, 36). For example, adhesion of AML cells is mediated by the interactions of VLA-4 and VLA-5 with extracellular matrix fibronectin as well as via both VLA-4 and LFA-1 integrin interactions with stromal cells (33, 34). Leukemic cells interact with the hematopoietic microenvironment in many ways similar to normal precursors (32). It is usually associated with egress of blasts into the circulation and in some AML subtypes dissemination to extramedullar hematopoietic organs such as spleen and liver. Another study reported a correlation between lower levels of SDF-1 and CXCR4 expression in the periphery and higher mobilization rates of immature CD34 + cells in patients treated with Cy and granulocyte colony-stimulating factor (24).Īcute myelogenous leukemia (AML) is characterized by uncontrolled proliferation within the BM of myeloid progenitors arrested in their maturation process. Higher CXCR4 expression or in vitro migratory ability were correlated with faster hematological recovery in patients after allogeneic and autologous CD34 + cell transplantation or in juvenile patients transplanted with cord blood (CB) cells (21, 22, 23). These observations in murine models are of clinical relevance because several studies revealed a correlation between CXCR4 expression and stem cell motility in humans. BM SDF-1 degradation by proteolytic enzymes causes the release of progenitor and mature cells from the BM into the peripheral blood (PB) during granulocyte colony-stimulating factor-induced mobilization (19, 20). Disruption of SDF-1/CXCR4-mediated cell anchorage results in egress of cells into the circulation (17, 18). In addition, SDF-1/CXCR4 interactions participate in controlling the retention of hematopoietic cells within the BM and their release into the circulation (15, 16). Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose- and time-dependent manner. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2m null mice. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. ![]()
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