Focusing on CML

Chronic Myelogenous Leukemia (CML) is a hematopoietic stem-cell neoplasm of myeloid origin. A common method for the diagnosis of CML is based on the detection of a chromosomal translocation, first discovered in 1960 by Peter C. Nowell at the University Of Pennsylvania School Of Medicine in Philadelphia. The presence of the translocation was termed the Philadelphia chromosome and was the first chromosomal abnormality positively linked to cancer. Because it is present in over 90% of patients with CML, the Philadelphia chromosome is recognized as the genetic hallmark of CML. The translocation in the Philadelphia chromosome results in the juxtaposition of a portion of the BCR (breakpoint cluster region) gene located on chromosome 22 next to the ABL (Abelson leukemia virus) gene on chromosome 9 [t(9:22)]. Following the discovery of the Philadelphia chromosome came the finding that the product of the ABL gene function ed as a protein tyrosine kinase and that inappropriate regulation of kinase enzymes can be oncogenic. The BCR-ABL fusion protein was shown to be oncogenic and exhibit constitutive kinase activity. Constitutive kinase activity promotes the activation of a number of signaling pathways that support the uncontrolled growth and survival of hematopoietic cells resulting in neoplastic disease. These findings prompted a search for agents that could selectively target the activity of the BCR-Abl fusion protein and resulted in the identification of imatinib mesylate (Gleevec), the first tyrosine kinase inhibitor successfully and effectively used as a molecularly-targeted treatment for cancer. Thus, the discovery that began in Philadelphia with CML has served as a prime example of the successful translation of knowledge gained at the bench of basic scientists into treatments at the bedside of cancer patients.

Selected Reviews

Bumbea, H., Vladareanu, A. M., Voican, I., Cisleanu, D., Barsan, L., & Onisai, M. (2010). Chronic myeloid leukemia therapy in the era of tyrosine kinase inhibitors--the first molecular targeted treatment. J. Med. Life, 3, 162-166.

Koretzky, G. A. (2007). The legacy of the Philadelphia chromosome. J. Clin. Invest, 117, 2030-2032.

Sawyers, C. L. (1999). Chronic myeloid leukemia. N. Engl. J. Med., 340, 1330-1340.

CML Antibody Portfolio
 
Axl, BCR, cAbl, NUP98, SMARCB1/SNF5