Chromosomal translocations 9 22 Philadelphia chromosome

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

O A chromosomal translocation, the Philadelphia chromosome, is responsible for chronic myelogenous leukemia (CML). 

A well-known use of molecular methods is in the study of chromosomal translocations. Thus, in Philadelphia chromosome (ph1) positive chronic myelogenous leukemia (CML), the C-abl oncogene on chromosome 9 is translocated to a region on chromosome 22 called the breakpoint cluster region, or bcr. This (t9 22) translocation results in production of an abnormal fusion protein... 

Chronic myeloid leukemia (CML) occurs when there is a translocation of chromosomes 9 and 22 (also called Philadelphia translocation—a chromosomal abnormality). These two different chromosomes break off and reattach on the opposite chromosome. A consequence is that the activity of the Bcr-Abl gene, which encodes the enzyme tyrosine kinase, is turned on all the time. With this heightened activity, high levels of white blood cells are produced in the bone marrow. 

Spectral karyotyping involves the use of five different fluorescent probes that hybridize differentially to different sets of chromosomes. In combination with special cameras and image-pro-cessing software, this technique produces a karyotype in which every chromosome is painted a different color. This aDows the ready visualization of chromosome rearrangements such as small translocations (e.g., the Philadelphia chromosome rearrangement discussed above). 

Cytogenetic analysis of patients with chronic myelogenous leukemia (CML) reveals an unusual translocation between chromosomes 9 and22 termed the Philadelphia chromosome."... 

Fig. 14.4. Formation of a hybrid oncoprotein, illustrated by translocation of the Abl tyrosine kinase. The gene for the Ser-spedfic protein kinase BCR is fused with a part of the c-abl gene in the process of the Philadelphia chromosome translocation. Fusion genes are produced on chromosome 22, coding for various fusion proteins. The most important fusion proteins are the p -and p -BCR-Abl hybrid proteins, which have increased Tyr kinase activity and an altered subcel-lular location.

The first chromosome abnormality found to be associated with a cancer was the Philadelphia chromosome, which arises as a result of a reciprocal translocation between chromosomes 9 and 22 (fig. S4.4). The tumor associated with this translocation is chronic myelogenous leukemia and results from the activation of the c-abl oncogene, which is normally located on chromosome 9. 

The Philadelphia chromosome arises by a reciprocal translocation between chromosomes 9 and 22. Note that the abl protooncogene is moved in the translocation process. 

Imatinib (STI571) is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9 22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent inhibits other activated receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit. 

Imatinib. Chronic myelogenous leukemia (CML) results from a genetic defect in the hematopoietic stem cells of the bone marrow. Nearly all CML patients possess the Philadelphia chromosome. It results from translocation between chromosomes 9 and 22 of the c-abl protooncogene, leading to the hybrid bcr-abl fusion gene on chromosome 22. The recombinant gene encodes a tyrosine kinase mutant with unregulated (constitutive), enhanced activity that promotes cell proliferation. Imatinib is a tyrosine kinase inhibitor that specifically affects this mutant but also interacts with some other kinases. It can be used orally in Philadelphia chromo-some-positive CML. 

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