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The exact cause of chronic myelogenous leukemia (CML) is not currently known but research over the past 40 years has expanded our understanding about the genetic and molecular events that lead to the development of chronic myelogenous leukemia. The major genetic abnormality that is observed in the bone marrow cells of more than 90% of patients with chronic myelogenous leukemia is the Philadelphia chromosome, also known as the Ph chromosome.

In 1960, doctors at the University of Pennsylvania School of Medicine in Philadelphia discovered that patients with chronic myelogenous leukemia had an abnormal chromosome (chromosome 22) that was much shorter in length than the same chromosome in healthy people. They named this abnormally short chromosome as the Philadelphia (Ph) chromosome. In 1973, researchers discovered that blood cells from patients with chronic myelogenous leukemia also exhibited another abnormal chromosome (chromosome 9). Subsequent research has led to a better understanding of the role of these two abnormal chromosomes in the development of chronic myelogenous leukemia. The specific mechanism involved is an abnormal genetic translocation (exchange) of broken chromosome pieces between chromosome 9 and chromosome 22. In more technical terms, this is referred to as the t(9;22) translocation. The consequence of this abnormal t(9;22) translocation is the creation of an abnormal fusion gene called BCR-ABL. The creation of the abnormal BCR-ABL fusion gene, in turn, results in the production of an abnormal fusion protein called tyrosine kinase, an enzyme that promotes leukemic transformation (leukemia resulting from the uncontrolled production and accumulation of white blood cells).

Scientists still do not fully understand what triggers the initial steps leading to the eventual development of chronic myelogenous leukemia. Although it is clear that broken pieces from chromosome 9 and chromosome 22 translocate and lead to the creation of the abnormal BCR-ABL fusion gene, just what causes pieces of these chromosomes to break off is not well understood. Epidemiological studies have shown that people who have been exposed to high levels of ionizing radiation, such as survivors of the atomic bombs dropped on Japan during World War II, developed an increased risk of chronic myelogenous leukemia. It is also thought that radiation therapy for certain types of cancers such as thyroid cancer or lymphomas may slightly increase a person's risk for developing chronic myelogenous leukemia. It is important to emphasize, however, that most people who develop chronic myelogenous leukemia have no know risk factors for the disease and research is ongoing to try to better understand why people develop the disease.