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Cancer: CML and the Philadelphia chromosome


Like all neoplastic disorders, chronic myelogenous leukemia (CML) is characterized by the loss of important regulatory factors controlling cell growth, differentiation, proliferation, and/or cell death. The dysregulation that occurs in CML is due to the development of a unique chromosomal abnormality, commonly referred to as the “Philadelphia chromosome”. The presence of this genetic aberration is important in differentiating CML from other pathological disorders such as a leukemoid reaction. The term ‘leukemoid reaction’ simply refers to the body’s normal response to many infections, leading to a proliferation of leukocytes (leukocytosis), which may resemble CML under the microscope.
The Philadelphia chromosome arises from a translocation between chromosomes 9 and 22, producing an elongated chromosome 9, and a truncated chromosome 22, as shown in Figure 1. The result of this t(9;22) change is the fusion of the Bcr (breakpoint cluster region) gene on chromosome 22 with the Abl1 gene of chromosome 9. In its normal position, the Abl1 gene codes for a membrane-associated tyrosine kinase that is regulated by an autoinhibitory R domain. The Philadelphia translocation product gives rise to hybrid Bcr-Abl mRNA and, subsequently, a BCR-ABL fusion protein lacking the R domain.
Figure 1 The Philadelphia chromosome caused by reciprocal translocation of chromosomes 9 and 22
The chemotherapeutic agent imatinib functions as a highly specific inhibitor of BCR-ABL. Imatinib is part of a larger family of tyrosine kinase inhibitors (TKIs). Imatinib is a very effective treatment option for patients with CML, who most often harbor a Philadelphia chromosome. Figure 2 shows the rate of ATP hydrolysis by BCR-ABL in the presence and absence of imatinib.
Figure 2 Activity of BCR-ABL as measured by its hydrolysis of ATP
Which scenario is most likely in the cells of a patient with the Philadelphia chromosome?
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