STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.

The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.

In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.

Imatinib has revolutionized drug therapy of chronic myeloid leukemia (CML).

Human Ph + leukemias are caused by the BCR-ABL1 oncogene and include CML and B-ALL. CML has a triphasic clinical course, with chronic and accelerated phases followed by a terminal blast crisis phase resembling acute leukemia, in which myeloid or lymphoid blasts fail to differentiate. Together, lymphoid blast crisis of CML and Ph + B-ALL account for 20% of adult cases and 5% of pediatric cases of acute lymphoblastic leukemia. One-half of adult and 20% of pediatric BALLs express the p210 isoform of Bcr-Abl, and the remainder express the p190 isoform 1,2 . Whereas the Abl tyrosine kinase inhibitor imatinib mesylate induces a complete hematologic response in nearly all individuals with chronic phase CML 3 , imatinib is much less effective in treating CML blast crisis and Ph + B-ALL 2 owing to acquired resistance [4][5][6][7] . Drugs that target essential signaling molecules downstream of Bcr-Abl may help overcome or prevent imatinib resistance.Bcr-Abl activates multiple signaling pathways, including Ras, MAPK, STAT, JNK/SAPK, PI-3 kinase, NF-kB and c-Myc 8 . Furthermore, in myeloid cell lines Bcr-Abl activates the Src family kinases Lyn and Hck 9 . Multiple domains of Bcr-Abl interact with and activate Src kinases independently of Bcr-Abl kinase activity [10][11][12] , and studies with dominant-negative mutants and Src inhibitors suggest that Src kinases may contribute to the proliferation and survival of myeloid cell lines expressing Bcr-Abl in vitro [13][14][15] . Results in cell lines expressing Bcr-Abl often do not correlate with leukemogenesis in vivo 16 , emphasizing the need to evaluate signaling pathways in an animal model of leukemia. We developed accurate and quantitative mouse models of chronic phase CML 17 and Ph + B-ALL 17,18 . Here, we use these models to show that Src kinases are required for the induction of B-ALL by Bcr-Abl but are dispensable for induction of CMLlike myeloproliferative disease. RESULTS Bcr-Abl activates Lyn, Hck and Fgr in pre-B cellsBcr-Abl interacts with and activates the Src kinases Lyn and Hck in myeloid cells 9 . We investigated whether Bcr-Abl also activates Src kinases in pre-B lymphoid cells. We found Bcr-Abl protein and abundant tyrosine-phosphorylated cell proteins in BL-2 cells (isolated from a mouse with Bcr-Abl-induced B-ALL) and in ENU48515 cells (an N-ethyl-N-nitrosourea (ENU)-induced pre-B leukemia mouse line) transduced with BCR-ABL1 retrovirus, but not in vector-transduced cells (Fig. 1a). Of the eight Src family kinases expressed in hematopoetic cells (Blk, Fgr, Fyn, Hck, Lck, Lyn, c-Src and Yes), parental ENU48515 cells had moderate levels of constitutively activate Fyn and Lyn, and Bcr-Abl expression increased the activation of Lyn and also activated five other Src kinases (Blk, Fgr, Hck, Lck and c-Src), as indicated by increased tyrosine phosphorylation (Fig. 1b). Phosphorylation of Fyn was not increased with BcrAbl expression in ENU48515 cells, and Yes was not expressed. In primary leukemic cells isolated from peripheral blood of mice with

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These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo.