Bcr-Abl is a chimeric oncoprotein that is strongly implicated in acute lymphoblastic (ALL) and chronic myelogenous leukemias (CML).In 1960, Nowell and Hungerford identified an abnormally small chromosome in patients with chronic myelogenous leukemia (CML) (Nowell and Hungerford 1960). This abnormal chromosome, which is known as the Philadelphia (Ph 1 ) chromosome, was later identified as the result of a reciprocal translocation between the bcr gene on chromosome 22 and the abl gene on chromosome 9. The fusion of the bcr and abl genes produces a chimeric protein known as Bcr-Abl (Kurzrock et al. 1988;Rosenberg and Witte 1988;Ramakrishnan and Rosenberg 1989). Three different fusion sites result in the formation of different Bcr-Abl protein products named p185, p210, and p230, each differing in the amount of bcr-encoded sequences they contain (Wada et al. 1995;Melo 1996; Pane et al. 1996). p185 Bcr-Abl has been observed in 15%-25% of patients with a very aggressive, short latency leukemia known as acute lymphoblastic leukemia (ALL). The p210 form of Bcr-Abl is the causative mutation in 95% of cases of CML, a less aggressive and longer latency disease (Ramakrishnan and Rosenberg 1989). A 230-kD protein (p230) is the most recent form of Bcr-Abl discovered and is associated with a mild chronic neutrophilic leukemia (Wada et al. 1995; Pane et al. 1996).The ability of Bcr-Abl to initiate leukemogenesis has been established through extensive studies in cell culture and animal models (Daley et al. 1990;Heisterkamp et al. 1990;Voncken et al. 1995). Bcr-Abl is a deregulated tyrosine kinase that transforms both fibroblasts and hematopoietic cells in culture and cells transformed by Bcr-Abl can form tumors in nude mice (Daley and Baltimore 1988;Pendergast et al. 1993b; Afar et al. 1994;Cortez et al. 1995). Irradiated mice transplanted with bone marrow cells expressing Bcr-Abl produce a myeloproliferative disease resembling CML (Daley et al. 1990

Rac is a member of the Ras superfamily of GTPases and functions as a GDP/GTP-regulated switch. Formation of active Rac-GTP is stimulated by Dbl family guanine nucleotide exchange factors (GEFs), such as Tiam1 (ref. 2). Once activated, Rac stimulates signalling pathways that regulate actin organization, gene expression and cellular proliferation. Rac also functions downstream of the Ras oncoprotein in pathways that stimulate membrane ruffling, growth transformation, activation of the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase, activation of the NF-kappa B transcription factor and promotion of cell survival. Although recent studies support phosphatidylinositol 3-OH kinase (PI(3)K)-dependent mechanisms through which Ras might activate Rac (refs 9,10), the precise mechanism remains to be determined. Here we demonstrate that Tiam1, a Rac-specific GEF, preferentially associates with activated GTP-bound Ras through a Ras-binding domain. Furthermore, activated Ras and Tiam1 cooperate to cause synergistic formation of Rac-GTP in a PI(3)K-independent manner. Thus, Tiam1 can function as an effector that directly mediates Ras activation of Rac.

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