Proteins BCR-ABL

Abstract The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Imatinib, a 2-phenylamino-pyrimidine Bcr-Abl inhibitor developed by Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patients with early stage disease. However, patients with advanced disease often become resistant to imatinib. The predominant form of this resistance is the development of mutations in the Bcr-Abl protein. These point mutations can be amino acid residues that make direct contact with imatinib or residues that do not allow Bcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation of the protein, both types of mutations prevent this inhibitor from binding. Several approaches have been taken to identify additional... 

The molecular mechanism behind imatinib resistance mirrors its molecular mechanism of action. Bcr-Abl gene duplication as well as transcriptional mechanisms leading to increases in Bcr-Abl transcript levels can lead to imatinib resistance. Thus, the Bcr-Abl inhibition exerts selective pressure on CML tumors to increase Bcr-Abl signaling, which is manifest by upregulation of Bcr-Abl messenger RNA. Another common mechanism of resistance is the mutation of the Bcr-Abl kinase ATP-binding pocket in which imatinib binds [11]. The mutation in the ATP-binding pocket produces a Bcr-Abl protein kinase, which can carry out ATP-dependent substrate phosphorylation but... 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

Gleevec ) is a tyrosine kinase inhibitor used as first-line therapy in the majority of patients with CML. As a potent tyrosine kinase inhibitor, imatinib inhibits phosphorylation of various proteins involved in cell proliferation. Imatinib works by binding to the ATP-binding pocket of BCR-ABL.7 The drug induces complete hematologic responses in more than 95% of patients and complete cytogenetic responses in about 80% of patients in chronic phase.8 Most patients have traces of the disease when measured by RT-PCR and are not cured of their disease. 

Keywords Tyrphostins, Protein tyrosine, Kinases, JAK-2 EGF, PDGF BCR-ABL, Psoriasis, Papilloma, Restenosis, Leukemia, Lymphoma... 

Imatinib mesylate (Gleevec, Novartis Glivec in countries other than the United States) is a drug for the treatment of chronic myeloid leukemia (CML). CML is a result of a chromosomal problem and gives rise to high levels of white blood cells. An enzyme called BCR-ABL is involved. The BCR-ABL gene encodes a protein with elevated tyrosine kinase activity (see Exhibit 7.3). 

Sattler, M., Salgja, R., Shrikhande, G., Verma, S., Choi, J.L., Rohrschneider, L.R., and Griffin, J.D., 1997, The phosphatidyhnositol polyphosphate 5-phosphatase SHIP and the protein tyrosine phosphatase SHP-2 form a complex in hematopoietic cells which can be regulated by BCR/ABL and growth factors. Oncogene, 15 2379-2384. 

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