**Abstract**

The aberrant tyrosine phosphorylation, either due to constitutive tyrosine kinases (TKs) or to inactivation of protein tyrosine phosphatases (PTPs), is a widespread feature of many cancerous cells. The BCR-ABL fusion protein, which arises from the Philadelphia chromosome, is a molecular distinct and peculiar trait of some kind of leukemia, namely Chronic Myeloid and Acute Lymphoblastic Leukemia, and displays constitutive tyrosine kinase activity. In the chapter, we will highlight the milestones that had led to the identification of the BCR-ABL fusion gene and its role as the only molecular pathogenic event sufficient to elicit and sustain chronic myeloid leukemia. We will also discuss the effort made to unveil the molecular mechanisms of action of the chimeric tyrosine kinase that eventually lead to aberrant cell proliferation and impaired cell-death. Furthermore, we will also review the lesson learned from the selective inhibition of BCR-ABL which currently represent a breakthrough in the treatment of several tumors characterized by defective tyrosine kinase activity.

**Keywords:** chromosomal translocation, fusion gene, tyrosine kinase, leukemia, tyrosine kinase inhibitors, targeted therapy

### **1. Introduction**

The up-regulated enzymatic activity of tyrosine kinases (TKs) is one of the most frequent events in human cancers. Basically, it is attributable to three distinct molecular-genetic mechanisms covering either the overexpression, the activating mutations or eventually chromosomal translocations involving tyrosine kinase genes. Therefore, targeting the kinases harboring oncogenic properties has led to prominent changes in cancer clinical management. An outstanding contribute in achieving the goal has been offered by the BCR-ABL oncogene, whose story started more than half a century ago. In the 1960s a couple of scientists working in Philadelphia described a major chromosomal abnormality in patients affected by Chronic Myeloid Leukemia (CML) [1, 2]. The chromosomal aberration consisted of an acrocentric chromosome that was originally thought as the outcome of a chromosomal deletion. At that time, it was the first chromosomal abnormality unambiguously associated to a specific malignancy. With the improvement of the chromosomal banding techniques, it became clear that the chromosome

abnormality was a shortened chromosome 22. Among a chorus of skepticism and wonder at the beginning of the seventies that short chromosome, that it is now known as Philadelphia chromosome (Ph), was identified as the product of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22). However, we had to wait until the eighties to know that the exact molecular consequence of the t(9;22) was a fusion gene encoding for a chimeric protein displaying constitutively tyrosine kinase activity. Altogether these discoveries delivered an outstanding message whereby a disease was tightly linked to a single oncogene, BCR-ABL. Since then, dozens of translocations have been found in other cancers, including acute promyelocytic leukemia.

BCR-ABL is a peculiar protein for several of reasons: 1) it is a chimeric protein that is encoded by a fusion gene deriving from a reciprocal chromosomal translocation; 2) it is a constitutively active tyrosine kinase eliciting oncogenic signals, 3) it has been the first oncogene associated to a disease displaying dual properties either as driver and in sustaining the neoplasm evolution, and 4) it has been the first kinase to be selectively targeted with small molecules, thus paving the way for the development of a number of tyrosine kinase inhibitors (TKIs).

In the present chapter we are going to discuss the milestones of a story, started 60 years ago, which has happily led to the selective pharmacological inhibition of BCR-ABL. Hence, CML, whose diagnosis was before a death sentence, is now successfully cured in the vast majority of the cases.
