Eileen Scigliano, MD
Mount Sinai School of Medicine, New York, NY
Copyright of the American Society of Hematology, 2006. ISSN: 1931-6860.
This case was reviewed and updated in March 2013 by Dr. Marc J. Kahn and members of the Teaching Cases Subcommittee.
What is the pathogenesis of CML?
In patients with CML, the hematopoietic cells contain a reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in two derivative chromosomes, 9q+ and 22q-, the latter referred to as the Philadelphia (Ph1) chromosome. This translocation results in the fusion of the cellular oncogene abl on chromosome 9 with the breakpoint cluster region gene bcr on chromosome 22. The identification of this characteristic translocation in granulocytic, erythrocytic, megakaryocytic and lymphocytic cells provides one line of evidence that CML arises from a single, multipotent stem cell. Glucose-6-phosphate-dehydrogenase (G6PD) enzyme studies further confirm the clonal origin of this malignancy by identifying a single isoenzyme type in neutrophils, monocytes, eosinophils, basophils, platelets, erythrocytes and B-lymphocytes from women with CML who are heterozygous for the G6PD enzyme.
The chimeric bcr-abl gene, which encodes a hybrid protein of 210 kDa with increased tyrosine kinase activity, is found in all CML patients and is believed to be central to the pathogenesis of CML. The BCR-ABL chimeric protein has been shown to induce cell proliferation, transform hematopoietic cells and suppress apoptosis in vivo. A CML-like disease has been induced in mice by introduction of the bcr-abl gene into bone marrow progenitors.
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