Chronic myelogenous leukemia CML

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. 

Explain the role of the Philadelphia chromosome in the pathophysiology of chronic myelogenous leukemia (CML). 

Chronic leukemia consists of a number of disorders, including chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL). 

A well-known use of molecular methods is in the study of chromosomal translocations. Thus, in Philadelphia chromosome (ph1) positive chronic myelogenous leukemia (CML), the C-abl oncogene on chromosome 9 is translocated to a region on chromosome 22 called the breakpoint cluster region, or bcr. This (t9 22) translocation results in production of an abnormal fusion protein... 

Imatinib was the first anticancer drug that specifically targets a molecular defect in tumor cells. It is a breakthrough drug for chronic myelogenous leukemia (CML). Others have followed and more are yet to come. 

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... 

Cytogenetic analysis of patients with chronic myelogenous leukemia (CML) reveals an unusual translocation between chromosomes 9 and22 termed the Philadelphia chromosome."... 

Indications Treatment of chronic hepatitis C, hairy-cell leukemia and AIDS-related Kaposi s sarcoma, as well as for the treatment of chronic phase, Philadelphia chromosome-positive chronic myelogenous leukemia (CML)... 

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 (2),5 marketed by Novartis since 2001, is the first tyrosine kinase inhibitor approved as a treatment for chronic myelogenous leukemia (CML). It inhibits the BCR-ABL kinase that is highly specific to leukemic cells. Dasatinib (3)6 and nilotinib (4)7 are two other BCR-ABL kinase inhibitors marketed by Bristol-Myers Squibbs and Novartis, respectively. They are effective for the treatment of imatinib-resistant CML patients. 

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. 

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