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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3364-3372. Prepublished online as a Blood First Edition Paper on January 28, 2008; DOI 10.1182/blood-2007-08-106583.
CHEMOKINES, CYTOKINES, AND INTERLEUKINS The small GTPase Ral mediates SDF-1–induced migration of B cells and multiple myeloma cellsDepartments of1 Pathology and 2 Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Chemokine-controlled migration plays a critical role in B-cell development, differentiation, and function, as well as in the pathogenesis of B-cell malignancies, including the plasma cell neoplasm multiple myeloma (MM). Here, we demonstrate that stimulation of B cells and MM cells with the chemokine stromal cell–derived factor-1 (SDF-1) induces strong migration and activation of the Ras-like GTPase Ral. Inhibition of Ral, by expression of the dominant negative RalN28 mutant or of RalBP
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
GAP, a Ral effector mutant that sequesters active Ral, results in impaired SDF-1–induced migration of B cells and MM cells. Of the 2 Ral isoforms, RalA and RalB, RalB was found to mediate SDF-1–induced migration. We have recently shown that Btk, PLC
2, and Lyn/Syk mediate SDF-1–controlled B-cell migration; however, SDF-1–induced Ral activation is not affected in B cells deficient in these proteins. In addition, treatment with pharmacological inhibitors against PI3K and PLC or expression of dominant-negative Ras did not impair SDF-1–induced Ral activation. Taken together, these results reveal a novel function for Ral, that is, regulation of SDF-1–induced migration of B cells and MM cells, thereby providing new insights into the control of B-cell homeostasis, trafficking, and function, as well as into the pathogenesis of MM. 