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Defective p38 Mitogen-Activated Protein Kinase Signaling Impairs Chemotaxic but not Proliferative Responses to Stromal-Derived Factor-1 in Acute Lymphoblastic Leukemia

¹ Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney and ² Department of Hematology, Westmead Hospital, Westmead, New South Wales, Australia

Requests for reprints: Linda J. Bendall, Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Darcy Road, Westmead, NSW 2145, Australia. Phone: 61-2-9845-9069; Fax: 61-2-9845-9102; E-mail: linda_bendall{at}wmi.usyd.edu.au.

The chemokine stromal-derived factor-1 (SDF-1) regulates leukemic cell motility and proliferation; however, the importance of these functions in the growth and dissemination of leukemia is unclear. We examined SDF-1–mediated responses of cells from 27 cases of acute lymphoblastic leukemia (ALL). Although cells from the majority of cases showed chemotactic and proliferative responses to SDF-1, a subset of cases did not undergo chemotaxis in response to SDF-1, while still demonstrating dependence on SDF-1 for proliferation in stroma-supported cultures. This chemotactic defect was associated with an absence of phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by SDF-1, and of SDF-1–induced augmentation of ß₁ integrin–mediated adhesion. Signaling through phosphoinositide 3-kinase and MEK was not affected. No correlation was observed between CXCR4 expression and chemotactic function, in vitro migration into bone marrow stromal layers, and engraftment of leukemic cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This study suggests that signaling through p38 MAPK is required for ALL cell chemotaxis but not for proliferation, and that the loss of a chemotactic response to SDF-1 does not impede engraftment in NOD/SCID mice.

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