The long-range objective of this research is to characterize the mechanisms that regulate the mobilization of hematopoietic progenitor cells (HPC) from the bone marrow to blood. Hematopoietic stem cell transplantation is a potentially curative therapy for patients with advanced hematological malignancies. Recently, mobilized peripheral blood HPC instead of bone marrow-derived HPC have been used because of reduced engraftment times and relative ease of collection. Current mobilization protocols utilizing granulocyte colony stimulating factor (G-CSF) alone are generally well tolerated but not universally effective and are often associated with co-mobilization of neoplastic cells. A better understanding of the mechanisms that regulate HPC mobilization may lead to the design of novel mobilization strategies that overcome these problems. Accumulating evidence suggests that interactions between stromal derived factor-1 (SDF-1, CXCL12) and its cognate receptor, CXCR4, may play a key role in regulating HPC and neutrophil trafficking from the bone marrow. Loss-of-function models for SDF-1 and CXCR4 have established a critical role for these genes in the migration of HPC from the fetal liver to bone marrow. More recently, gain-of-function mutations of the CXCR4 gene have been implicated in the pathogenesis of WHIM syndrome, a syndrome manifested, in part, by impaired neutrophil trafficking from the bone marrow. We recently showed that G-CSF treatment results in a significant decrease in SDF-1alpha protein in the bone marrow of wild type mice. Finally, treatment with AMD3100, a selective antagonist of CXCR4, induces rapid and robust HPC mobilization in mice and humans. Collectively, these data suggest a hypothesis in which disruption of SDF-1/CXCR4 signaling is a key step in HPC mobilization by G-CSF. The objective of this research is to test this hypothesis and define mechanisms by which mobilizing agents regulate SDF-1/CXCR4 signaling. The following specific aims are proposed. 1. We will determine whether gain-of-function mutations of the CXCR4 gene found in patients with WHIM syndrome are sufficient to induce impaired HPC and neutrophil trafficking from the bone marrow. 2. We will identify the mechanisms by which G-CSF regulates SDF-1 expression in the bone marrow. 3. We will determine whether disruption of SDF-1/CXCR4 signaling is a common final pathway by which diverse mobilizing agents mediate HPC mobilization.
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