BCR-ABL fusion

On May 10, 2001, the FDA approved a Novartis drug, Gleevec, a tyrosine kinase inhibitor that specifically targets the BCR/ABL fusion protein. 

Shimizu T, Miyakawa Y, Iwata S et al. A novel mechanism for imatinib mesylate (STI571) resistance in CML cell line KT-1 role of TC-PTP in modulating signals downstream from the BCR-ABL fusion protein. Exp Hematol 2004 32 1057-1063. 

Yamamoto M, Kurosu T, Kakihana K et al. The two major imatinib resistance mutations, E255K and T3151, enhance the activity of BCR/ABL fusion kinase. Biochem Biophys Res Commun 2004 319 1272-1275. 

Imatinib (STI571) is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9 22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent inhibits other activated receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit. 

Chronic myelogenous leukemia (CML) arises from a chromosomally abnormal hematopoietic stem cell in which a balanced translocation between the long arms of chromosomes 9 and 22, t(9 22), is observed in 90-95% of cases. This translocation results in expression of the Bcr-Abl fusion oncoprotein with a molecular weight of 210 kDa, which is constitutively expressed. The clinical symptoms and course are related to the white blood cell count and its rate of increase. Most patients with white cell counts over 50,000/ L should be treated. The goals of treatment are to reduce the... 

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. 

Radich JP, Gehly G, Gooley T, et al. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia results and implications in 346 patients. Blood 1995 5 2632-38. 

The chronic myeloid leukemias are characterized by translocations that lead to constitutive activation of tyrosine kinases. As mentioned earlier, the most common of these is the t(9 22)(q34 qll), resulting in the BCR/ABL fusion that is characteristic of CML. Up to seven different chromosomal translocations are associated with the chronic leukemias of myeloid/monocytic lineage, but all are charac-... 

Conventional cytogenetics, FISH, and RT-PCR have been reliably used for the laboratory detection of the t(9 22). RT-PCR detection is possible in up to 95% of cases, and may detect up to 10% of cases missed by conventional cytogenetics, and is an important modality for minimal residual disease detection. Recently, quantitative real-time PCR-based approaches have improved the ability to detect and quantify BCR-ABL transcripts in CML patients (Figure 39-15 Color Plate 4]). The recent availability the tyrosine kinase inhibitor imatinib mesylate for CML is an important development in the treatment of CML and further underscores the importance of methods for sensitive and specific identification and quantification of the BCR-ABL fusions in patients with a clinical suspicion of a CML. 

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...

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. 

Kreuzer KA, Lass U, Bohn A, Landt O, Schmidt CA. LightCycler technology for the quantitation of bcr/abl fusion transcripts. Cancer Res 1999 59 3171-4. 

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. 

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