Abl gene

Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001 293 876-880. 

Gorre, M.E., et al., "Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification," Science, 293, 876-880 (2001). 

Many of the Philadelphia-positive adult ALL cases (50-75%) have a different type of gene rearrangement. The gene fusion BCR/c-abl takes place after the breakpoints in intron 1 of the BCR gene and the common sequence of the C-abl gene (H2). 

H2. Herman, A., Heisterkamp, N., von Lindem, M., Bootsman, D., and Grosveld, G., Unique fusion of bcr and c-abl genes in Philadelphia chromosome-positive acute lymphoblastic leukemia. Cell (Cambridge, MA) 51, 33-40 (1987). 

Imatinib mesylate (Gleevec, Novartis Glivec in countries other than the United States) is a drug for the treatment of chronic myeloid leukemia (CML). CML is a result of a chromosomal problem and gives rise to high levels of white blood cells. An enzyme called BCR-ABL is involved. The BCR-ABL gene encodes a protein with elevated tyrosine kinase activity (see Exhibit 7.3). 

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. 

Since the enzymatic activity of the protein encoded by the BCR-ABL gene is responsible for the cancer, it is logical to search for ways to tnm off that activity. The most straightforward way to tnm off the activity of an enzyme is to discover an inhibitor of the enzyme. We need a molecnle that specifically binds to the enzyme and tnms it off. That is precisely what imatinib does it specifically binds to the tyrosine kinase encoded by the BCR-ABL gene and abolishes its activity. In effect, imatinib converts the cancer cells of CML into the functional eqnivalent of normal cells normal cells do not have the enzyme and the imatinib-treated CML cells do not... 

The translocation moves the c-ABL gene that encodes a tyrosine kinase from chromosome 9 to the breakpoint cluster region fBCRj of chromosome 22. 

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.

Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210BCR/ABL gene of the Philadelphia chromosome. Science 1990 247 824-830. 

Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N et al. Several types of mutations of the ABL gene ean be found in chronic myeloid leukemia patients resistant to STI571, and they ean pre-exist to the onset of treatment. B/oor/2002 100 1014-1018. 

Snyder, D.S., Wu, Y., Wang, J.L., Rossi, J.J., Swiderski, P., Kaplan, B.E. and Forman, S.J. (1993) Ribozyme-mediated inhibition of bcr-abl gene expression in a Philadelphia chromosome-positive cell line. Blood, 82,600-605. 

Figure 15.37. Formation of the Bcr-Abl Gene by Translocation. In chronic myologenous leukemia, parts of chromosomes 9 and 22 are reciprocally exchanged, causing the ber and abl genes to fuse. The protein kinase encoded hy the bcr-abl gene is expressed at higher levels in cells having this translocation than is the c-abl gene in normal cells.

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