C-abl gene

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). 

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.

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.

During the translocation, a part of the c-abl gene is fused to the first exon of the her gene (Fig. 14.5). The pl80BCR ABL hybrid protein demonstrates increased tyrosine kinase activity, and it has a changed subcellular location in that it is predominantly found in the cytosol, whereas c-Abl normally exerts its function in the nucleus. Nuclear c-Abl has been shown to have an important role in damage-induced apoptosis. It is found in a repressed state bound to retinoblastoma protein pRb during G0 and Gj. 

Van Etten RA (1999) Cycling, stressed-out and nervous cellular functions of c-Abl. Trends Cell Biol 9 179-186 Van Etten RA et al (1989) The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization. Cell 58 669-678... 

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. 

Fig. 2. Mechanisms causing resistance to antitumor treatment. ATM. ataxia telangiectasia gene, (Westphal et al., 1998 Xu and Baltimore, 1996), bcl-2/bax (Farrow and Brown, 1996, Zunino et al., 1997 Haq and Zanke, 1998), bcr/abl (McGahon et al., 1994), BCRP, breast cancer resistance protein (Doyle et d., 1998 Ross et al, 1999) bleomycin hydrolase (El-Deiry, 1997), BRCAl (Husain et al., 1998 Chen et al., 1998), BRCA2 (Chen et al., 1998 Chen et 1999), c-abl (White and Prives, 1999), c-jun (Sanchez-Perez and Perona, 1999), cytidine deaminase (El-Deiry, 1997), DNA poip, DNA polymerase p (Ochs et al., 1999), dihydrofolate reductase (Schimke, 1986), DT-diaphorase (Riley and Workman, 1992 Fitzsimmons et al., 1996 El-Deiry, 1997), EGR-1 (Ahmed et al., 1996), fos (Niimi et al., 1991), glucosylceramide synthase...

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. 

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. 

Wen, S.-T, Van Etten, R. A. (1997). The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes Dev. 11, 2456-2467. 

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