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Recent advances in therapeutic regimens targeting aberrant proliferation of leukemia cells have led to a decline in the mortality of patients with acute leukemia. Nevertheless, a number of patients still suffer from refractory disease or relapse, indicating that more innovative and effective therapeutic strategies are required to achieve superior outcomes. One of the major indicators of poor prognosis in leukemia patients is extramedullary infiltration or dissemination of leukemia cells. In particular, leukemia cell infiltration into the central nervous system is one of the major complications negatively influencing prognosis. However, little is known about the mechanisms responsible for extramedullary dissemination of leukemia cells compared to those responsible for solid tumor metastasis. The chemokine SDF1 (stromal derived factor-1) and its receptor CXCR4 regulate trafficking of normal hematopoietic stem cells (HSC) as well as metastasis of solid tumor cells. Similarly, the majority of acute myeloid leukemia (AML) cells express CXCR4 and migrate in response to SDF1, suggesting that the SDF1/CXCR4 axis may be involved in the dissemination of AML cells to various organs. A recent study also suggests that chemokine/chemokine receptor interactions orchestrate extramedullary dissemination in childhood AML. Moreover, signaling through the chemokine receptor CCR7 is crucial for infiltration of T-ALL cells in the central nervous system. Our recent studies indicate that internal tandem duplication mutations of the Flt3 gene (ITD-Flt3), found in patients with AML, significantly augments migration of hematopoietic cells by deregulating CXCR4 signaling that are qualitatively distinct from cells lacking ITD-Flt3 and facilitate their infiltration to visceral organs while decreasing their homing to the bone marrow. ITD-Flt3 regulates overlapping as well as functionally distinct signaling pathways down-stream of SDF1/CXCR4 compared to cells that do not harbor ITD-Flt3 mutations. The data suggest that ITD-Flt3 may facilitate dissemination of leukemia cells by modulating SDF1/CXCR4 signaling and that blocking this functional cross-talk between ITD-Flt3 and CXCR4 pathways may have therapeutic benefit. Therefore, genes differentially regulated by SDF1 specifically in ITD-Flt3 cells may represent key targets regulating aberrant migration by

Trafficking of Acute Leukemia Cells – Chemokine Receptor Pathways that Modulate Leukemia Cell Dissemination