C-abl oncogene

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... 

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. 

Oppi, C. S., Shore, K., and Reddy, P. (1987). Nucleotide sequence of testis-derived c-abl cDNAs implications for testis-specific transcription and abl oncogene activation. Proc. Nad. Acad. Sci. USA 84 8200-8204. 

Zakeri, Z. F., Ponzetto, C., and Wolgemuth, D. J. (1988). Translational regulation of the novel haploid-specific transcripts for the c-abl proto-oncogene and a member of the 70 kDa heat-shock protein gene family in the male germ line. Dev. Biol. 125 417-422. 

The oncogenes c-myc and c-abl are dominant to their wild-type alleles. Many tumors arise from oncogenes that show recessive behavior when compared with their wild-type alleles. Such is the case with the genetic locus implicated in the malady known as bilateral retinoblastoma,... 

At present, we can induce CML in mice with high efficiency, shown by 100% induction of CML in mice (14). The same CML disease could be induced in most of the inbred mouse strain including C57BL/6, BALB/c, and viable gene knockout mice strains (15). Because all recipients develop CML with a short latency (about 3 weeks), this provides an excellent model for evaluating therapeutic agents for CML treatment (15). As CML is derived from the hematopoietic stem cells which harbor BCR-ABL oncogene, CML leukemia stem cells can also be studied in this model (15). In conclusion, this retroviral model system pro-... 

Much of the interest in Abelson (Abl) tyrosine kinase (review Smith and Mayer, 2002) stems from its involvement in oncogenesis in rodents and in humans. Like many other nonreceptor tyrosine kinases, Abl tyrosine kinase may be converted by mutations into a dominant oncoprotein and may thus contribute to tumor formation. The wild-type form of the Abelson kinase is termed c-Abl the viral, oncogenic form is termed v-Abl. This mutated enzyme was first discovered as the oncogene of murine Abelson leukemia virus. Apart from the v-Abl enzymes, other oncogenic forms of the Abelson kinase exist. Chronic myelogenic leukemia in humans is caused by a chromosome translocation in which a fusion protein is created from Abl tyrosine kinase and a Bcr protein (cf. Chapter 14). The result is a greatly increased tyrosine kinase activity with very different regulatory properties, to which a causal role in the occurrence of this leukemia is attributed. 

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. 

Groffen, J. Heisterkamp, N. Reynolds, F.H., Jr. Stephenson, J.R. Homology between phosphotyrosine acceptor site of human c-abl and viral oncogene products. Nature, 304, 167-169 (1983)... 

Bernards, A. Paskind, M. Baltimore, D. Four murine c-abl mRNAs arise by usage of two transcriptional promoters and alternative splicing. Oncogene, 2, 297-304 (1988)... 

Goga A et al (1993) Oncogenic actiwition of c-ABL by mutation within its last exon. Mol Cell Biol 13 4967 4975 Goldberg Z et al (2002) Tyrosine phosphorylation of Mdm2 by c-Abl Implications for p53 regulation. EMBO J 21 3715 3727... 

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