Bcr-abl fusion gene

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. 

Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals biologic significance and implications for the assessment of minimal residual disease. Blood 1998 92 3362-7. 

Westbrook CA, Hooberman AL, Spino C> Dodge RK, Larson RA, Davey F, et al. Clinical significance on the BCR-ABL fusion gene in adult acute lymphoblastic leukemia a Cancer and Leukemia Group B Study (8762). Blood 1992 80 2983-90. 

Another example of a constitutively activated tyrosine kinase that results from a BCR-ABL fusion gene... 

The bcr-abl fusion gene produces a mutant tyrosine kinase that is involved in both the increased proliferation of the CML clone, and in the reduction in FAS-mediated apoptosis. The characterization of the adenosine triphosphate (ATP) binding site on the tyrosine kinase has led to a new class of inhibitors. The first of these inhibitors, imatinib mesylate (Gleevec), was approved in 2001 for patients in chronic phase who had failed interferon alfa (IFN-a), and in accelerated phase or blast crisis. It obtained additional FDA approval in 2002 for first-line treatment in newly diagnosed CML. The clinical results associated with imatinib have changed the way CML is treated, and will be discussed in more detail under the treatment section of this chapter. "... 

The importance of detecting the bcr-abl fusion gene product in CML patients after alloHSCT was studied in 346 patients and 634 collected blood samples. A positive polymerase chain reaction (PCR) 3 months or 36 months after transplant did not predict for relapse, but a positive PCR at 6 or 12 months after transplant was highly predictive." With this tool, it may be possible to identify patients who are at high risk for clinical relapse and to treat them with donor lymphocyte infusion or imatinib in an attempt to suppress or eradicate residual disease. 

Figure 39-14 Schematic representation of the BCR (22q 11) and ABL (9q34) genes involved in the t(9 22), which is characteristic of all CMLs and a subset of ALLs. The centromeric (cen) and teiomeric (tel) directions are indicated.The relative positions of the major breakpoint duster (M-BCR), the minor breakpoint duster (m-6CR), and the micro breakpoint duster regions (ft-BCR) are shown. The previously used alternative nomenclature for the BCR and ABL exons is included where relevant. In panel A, the exons of the BCR genes are depicted in black rectangles, and those of the ABL genes are depicted in white rectangles. In panel B, the configuration and varieties of the BCR-ABL chimeric fusions seen in CML are shown. In the lower part of panel B, the configuration and varieties of the BCR-ABL fusions seen in ALL are shown. The el-a2 transcript is most commonly detected in t(9 22)-positive ALL, while the b3-a2 and b2-a2 fusions are the most commonly detected in CML...

Among small-molecule TKIs, one of the more successful agents is imatinib mesylate. Imatinib mesylate is a TKI of the fusion oncoprotein Bcr-Abl, a gene product driving the development of chronic myelogenic leukemia (CML). A major reason for the effectiveness of Imatinib is CML transformation in many instances only requires Bcr-Abl. In these cases inhibition of Bcr-Abl activity is sufficient to provide long-term control of the disease. Solid tumors usually have multiple abnormal... 

The Philadelphia chromosome results in the formation of an abnormal fusion gene, BCR-ABL, that encodes an overly active tyrosine kinase. 

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.

Castellanos, A., Pintado, B., Weruaga, E., Arevalo, 1L, Lopez, A., Orfao, A., et al. (1997) A BCR-ABL(pl90) fusion gene made by homologous recombination causes B-cell acute lymphoblastic leukemias in chimeric mice with independence of the endogenous bcr product. Blood 90, 2168-2174. 

A tyrosine kinase encoded from abl (Abelson) gene, the fusion protein ABL-BCR is involved in inhibition of apoptosis in chronic myelogenous leukemia cells... 

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