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Chronic Myeloid Leukemia Pathophysiology

By , BPharm

The pathophysiology of chronic myeloid leukemia (CML) is important to understand so that we can tailor treatments to the specific characteristic of the disease. This helps to improve treatment outcomes and minimize general side effects of therapy, as targeted treatments for the condition can be introduced.

CML is a stem cell disease that involves the accumulation of myeloid precursor cells in the bone marrow and blood. These cells have a distinctive abnormality in the gene with a translocation of chromosome 9 and chromosome 22. This genetic abnormality leads to the production of the BCR-ABL oncogene which appears to have tyrosine kinase activity.

Genetic Abnormality

Chronic myeloid leukemia is linked to a genetic abnormality known as the Philadelphia chromosome, which involves a translocation of the chromosome. It was discovered in 1960 by Peter Nowell and David Hungerford in Philadelphia, Pennsylvania, and made CML the first cancer to be associated with a genetic mutation.

The chromosomal translocation involves reversed placement of certain chromosomes with the fusion of the breakpoint cluster region (BCR) in chromosome 22 and the ABL gene on chromosome 9. As a result, BCR-ABL gene can create phosphorylation reactions with tyrosine kinase and the protein p210 can be produced.

The formation of the BCR-ABL gene is abnormal and it is this change that is responsible for the transformation of a normal cell to a CML cell. As the abnormal cells in the bone marrow continue to divide and replicate, changes in the blood cell become evident.

Cell Development

Stem cells, myeloid stem cells, and myeloid blast cells are usually involved in the production of monocytes and granulocyte blood cells under normal circumstances in a healthy person. CML can develop from an abnormality in either the stem cells or the myeloid stem cells in the bone marrow.

The BCR-ABL protein interacts with the subunit of the interleukin 3-beta receptor, which activates a series of proteins that are involved in the regulation of the cell cycle. As a result, the rate of cell division and replication increases. Additionally, the BCR-ABL protein has an inhibitory effect on the repair of DNA in the body and, as a result, there may be some instability in the genes that increases the likelihood of further gene mutations.

Pathophysiology Research

It is clear that the BCR-ABL protein plays a pivotal role in causing chronic myeloid leukemia. A deeper understanding of the nature of the protein, particularly how it acts as a tyrosine kinase, would be useful to improve treatment outcomes with targeted therapies. For this reason, scientific research to investigate the pathophysiology of the condition is very beneficial.

An example of research on the pathophysiology of chronic myeloid leukemia that has resulted in positive outcomes is the discovery of the drug imatinib (STI571). This drug targets the action of tyrosine kinase and helps to control the progression of the condition to more advanced stages of the disease. As a result, it helps to improve the prognosis for patients with CML.

Reviewed by Susha Cheriyedath, MSc

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Last Updated: Aug 9, 2016

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