Chronic myelogenous leukemia, oncogenes

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... 

Like many other nonreceptor tyrosine kinases, Abl tyrosine kinase may be converted by mutations into a dominant oncoprotein and thus contribute to tumor formation. Abl tyrosine kinase was first discovered as the oncogene of murine Abelson leukemia virus. Chronic myelogenic leukemia in humans is cause by a chromosome translocation in which a fusion protein is created of Abl tyrosine kinase and a Bcr protein (c Chapter 14). The result is a greatly increased tyrosine kinase activity, to which a causal role in occurrence of this leukemia is attributed. 

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. 

FIGURE 132-1. Diagram of the chromosomal translocation that results in the Philadelphia chromosome. This abnormality is encountered in 90% to 95% of patients who have chronic myelogenous leukemia. (From Fishleder AK. Oncogenes and cancer clinical applications. Cleve Clin J Med 1990 57 721-726.)... 

Pinilla-lbarz, J, Cathcart K, Korontsvit T, Soignet S, Bocchia M, Caggiano J, Lai L, Jimenez J, Kolitz J, Scheinberg DA. Vaccination of patients with chronic myelogenous leukemia with bcr-abi oncogene breakpoint fusion peptides generates specific immune responses. Blood 2000 95(5) 1781-1787. 

The prototype molecularly targeted therapeutic agent is imatinib, an inhibitor of the Bcr-Abl tyrosine kinase. This oncogenic kinase is produced by translocation of the Bcr locus on chromosome 9 to the c-Abl tyrosine kinase on chromosome 11, termed the Philadelphia chromosome because of its discovery in 1960 at the University of Pennsylvania School of Medicine by Peter Nowell and David Hungerford from the Institute for Cancer Research [9]. It was later demonstrated in 1973 by Janet Rowley that the Philadelphia translocation was responsible for a specific form of leukemia, chronic myelogenous leukemia (CML) [10], In 2001, imatinib was approved for treatment of CML patients, and produced remarkable results with more than 92% patients achieving 14-month progression-free survival on imatinib as a monotherapy. 

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