Chronic Myelocytic Leukemia - Part I: History, Clinical Presentation, and Molecular Biology

Clinical Laboratory Science, Winter 2005 by Randolph, Tim R

In AML:M3 the mutation is the t(15:17) translocation involving the PML/RARα genes, and in CML it is the t(9;22) translocation forming the Philadelphia chromosome that produces the BCR/ABL fusion gene. The phenomenon of full leukemogenic transformation from a single mutation makes both AML:M3 and CML leukemogenic paradigms. In addition, the discovery of single mutation transformations and their impact on leukemogenesis resulted in the development of tailored, single agent therapies targeting the products of these mutations, creating a therapeutic paradigm.

HISTORICAL ORIGIN OF CML

The first scientific description of CML is credited to John Hughes Bennett in Edinburgh in 1845.1 However, patients with vague but similar symptoms can be found in the French literature as early as 1825. It is possible that some of these earlier patients may have also suffered from CML. For example, Velpeau reported a case of a 63-year-old woman who, at autopsy, was found to have an enormous spleen and whose blood was "thick like gruel such that one might have asked if it were not rather laudable pus, than blood".2 Later in 1839 the French microscopist Paul Donne' described a 44-year-old woman who presented at autopsy with an enlarged spleen and whose blood seemed "semipurulent under the microscope with more than half of die cells appearing to be white globules".s Nevertheless, Bennett's description was more complete and scientific in nature thereby earning him credit as the first description of CML. Bennett became interested in the disorder when his mentor, Dr David Craigie, observed two patients admitted to the Royal Infirmary in Edinburgh with unusual blood consistency and a splenic tumor. The first patient was observed in 1841 but was dismissed as unusual until 1844 when a 28-year-old man presented with similar symptoms. John Bennett was given permission to perform an autopsy and study the pathology of this second case. His report entitled "case of hypertrophy of the spleen and liver in which death took place from supperation of the blood" was published in the Edinburgh Medical and Surgical Journal in October 1845.1

In the same year, Robert Virchow, a 24-year-old graduate of the Berlin Army Medical School, observed his first case of CML while studying the pathology of phlebitis. A 50-yearold woman was admitted to the Charite' Hospital in Berlin complaining of fatigue, nosebleeds, swelling of the legs and abdomen, and died within four months. Virchow noted the enlarged spleen and liver, but also described blood vessels full of material resembling pus. In 1847 Virchow suggested the term "leukamie" for the disorder, meaning white blood, but it did not achieve universal approval because many physicians agreed that "blood was never white".3 In 1852, Bennett recommended the term "leucocythemia", meaning increased white blood cells, which was better accepted, especially in light of the 37 cases Bennett had described to date.4 In 1856, Virchow was credited with concluding that the disorder was not the result of an infectious process but rather was caused by the tissue that produced the white cells. He also categorized two types of chronic leukemia, splenic and lymphatic, which we now know as leukemia and lymphoma, respectively.1