Bcr-Abl oncoprotein

Several cell lines were screened for their response to three standard chemotherapy drugs fludarabine, vincristine, and Gleevec decreases in the mean optophoretic distance of Bcr-Abl positive cell line K-562 with no effect in the other cell lines demonstrate that the downshift in mean displacement is specific to the presence of the Bcr-Abl oncoprotein fludarabine, however, was ineffective in causing a decrease in the optophoretic displacement of the K-562 cell line, but showed an effect in the other four cell lines mobility values for each cell in the population have been taken and averaged, but data on subsets of the cells can still be extracted and further analyzed. 

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. 

Fig. 15.1. Signal pathways activated or inhibited by BCR-ABL oncoprotein. The figure shows some of all the downstream signalling pathways of BCR-ABL note, more molecules which interact with BCR-ABL have been reported. GRB2, growth factor receptor-bound protein 2 PI3K, phosphatidylinositol 3-kinase ICSBP, interferon consensus sequence binding protein.

Figure 13-17. A simpUfled representation illnstrating the likely mode of action of STI571 or Gleevec . STI571 inhibits the binding of adenosine triphosphate (ATP) to the kinase activation domain of Bcr-Abl oncoprotein [64-66].

McWhirter JR, Galasso DL, Wang JY. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol 1993 13 7587-95. 

In hematopoietic cehs, cytokines also regulate death receptor-mediated pathways. Hematopoietic cytokines, such as IL-3 and erythropoietin in normal cells and BCR-ABL oncoprotein in transformed cells, inhibit transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The inhibition of TRAIL function is sufficient to partially rescue cytokine-deprived cells from apoptosis. Cytokine and BCR-ABL suppression of TRAIL transcription is mediated through phosphorylation and inhibition of the forkhead F0X03a transcription factor. BCR-ABL-induced inhibition of TRAIL transcription in hematopoietic cells may provide a novel mechanism for tumorigenicity in chronic myeloid leukemia. ... 

BCR/ABL oncoprotein induces an oncogenic cascade at multiple levels, some quite ancient. 

MeWhirter JR, Wang JY (1993) An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. EMBO J 12 1533-1546... 

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.

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 mesylate (Gleevec , Novartis) is a small-molecule compound that inhibits a specific tyrosine kinase enzyme, the Bcr-Abl fusion oncoprotein. It is used for gastrointestinal stromal tumor and chronic myeloid leukemia. 

Cell Survival and Proliferation Signaling Pathways Active in Cancer and Their Role in Tumor Growth 25 Abl Pathway 25 BCR-ABL Chimeric Oncoprotein and Its Oncogenic Effects 26 Major Signal Transduction Pathways Activated by ABL/BCR-ABL 28 PI3-K/Akt Pathway 28 Anti-Apoptotic Actions ofAKT 29... 

Fig. 2.3. Major signaling pathways activated by BCR-ABL. Multiple signaling pathways become activated by the consti-tutively active chimeric fusion oncoprotein. (See main text for further details)...

Lagasse E et al (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6 1229-1234 LaMontagne KR Jr et al (1998) Protein tyrosine phosphatase IB antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo. Mol Cell Biol 18 2965-2975 Laneuville P (1995) Abl tyrosine protein kinase. Semin Immunol 7 255-266... 

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... 

Like many other nonreceptor tyrosine kinases, Abl tyrosine kinase may be converted by mutations into a dominant oncoprotein and thus contribute to tumor formation. Abl tyrosine kinase was first discovered as the oncogene of murine Abelson leukemia virus. Chronic myelogenic leukemia in humans is cause by a chromosome translocation in which a fusion protein is created of Abl tyrosine kinase and a Bcr protein (c Chapter 14). The result is a greatly increased tyrosine kinase activity, to which a causal role in occurrence of this leukemia is attributed. 

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