What is the pathophysiology of chronic myelogenous leukemia (CML)?

Updated: May 23, 2021
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, FACP  more...
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Answer

CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)]. The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph1) chromosome after the city of discovery. (See the image below.)

The Philadelphia chromosome, which is a diagnostic The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.

This translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype, through processes that are not yet fully understood. [3, 4, 5, 6, 7, 8, 9, 10, 2]

The presence of BCR/ABL rearrangement is the hallmark of CML, although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.

The initiating factor of CML is still unknown, but exposure to ionizing radiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki. Other agents, such as benzene, are possible causes.


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