ABSTRACT
The efficacy of imatinib, a selective ABL-kinase inhibitor, for the treatment of chronic myeloid leukemia (CML) has set a paradigm for translational research in oncology. 1,2 This success would have been impossible without a detailed understanding of the molecular pathogenesis of CML, a story that took more than 150 years to unravel. CML was described in 1845 independently by Bennett and Virchow. 3,4 Progress was moderate for more than a century, until in 1960 Nowell and Hungerford reported the presence of a small (minute) chromosome 22 (22q − ) in seven CML patients, 5 which was named the Philadelphia chromosome (Ph), according to the city of its discovery. The next four decades saw the identification of the (9;22)(q34;q11) reciprocal translocation by Janet Rowley and colleagues, and the identification of BCR and ABL genes as the translocation partners by Groffen and Bartram, respectively ( Figure 2.1 ). 6-8 Even before the recognition of the BCR-ABL fusion it had been known that ABL is an oncogene. When studying the Moloney murine leukemia virus (M-MuLV) in neonatal mice, Abelson and Rabstein discovered a retrovirus with different oncogenic potential, which they termed Abelson-murine leukemia virus (A-MuLV). 9,10 Additional studies showed that the virus contained GAG sequences fused upstream of murine ABL. 11 Around the same time Collett and Erikson reported a correlation between the protein kinase activity of the Rous sarcoma virus (RSV) SRC protein and its transforming potency, which was subsequently characterized as specific tyrosine kinase activity by Hunter
and Sefton. 12,13 The discovery that v-ABL is a tyrosine kinase and that the transforming potency of BCR-ABL is dependent on its tyrosine kinase activity led to the concept that transforming oncogenes can dysregulate target cells via aberrant tyrosine phosphorylation. 14,15 Recognizing the central role of BCR-ABL for disease pathogenesis, the World Health Organization has defined CML as a BCR-ABL - positive myeloproliferative disorder.
