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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.

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CHEMOKINES, CYTOKINES, AND INTERLEUKINS

The small GTPase Ral mediates SDF-1–induced migration of B cells and multiple myeloma cells

David J. J. de Gorter1, Rogier M. Reijmers1, Esther A. Beuling1, Hildegonda P. H. Naber1, Annemieke Kuil1, Marie José Kersten2, Steven T. Pals1, and Marcel Spaargaren1

Departments 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{Delta}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{gamma}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.


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