Chronic myeloid leukaemia: discovery of the Philadelphia chromosome

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07/08/23

A review of: Chromosome studies on normal and leukemic human leukocytes. Nowell PC, Hungerford DA. J Natl Cancer Inst. 1960 Jul;25:85-109.

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Leukaemia, cancer of the blood, affects white blood cells and causes proliferation of bone marrow white blood cell progenitors, haematopoietic cells, initiating mass production of faulty white blood cells. This throws off the balance between leukocytes, erythrocytes and platelets in the blood. There are several different types of leukemia such as chronic lymphocytic leukaemia, acute lymphocytic leukaemia, acute myeloid leukaemia, and chronic myeloid leukaemia. The main difference between myeloid and lymphocytic variants is the type of white blood cell affected.

In the 1950s leukaemia had a 5-year survival rate of only 14% - a breakthrough was clearly needed, a breakthrough that was going to come from the University of Pennsylvania. Peter Nowell and David Hungerford analysed the leukocyte chromosomes of chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) patients, and found “a definite abnormality, probably involving the Y chromosome” in two patients suffering from CML. Named after the city in which it was discovered, this “Philadelphia chromosome” was created via a reciprocal translocation involving chromosomes 9 and 22, not related to the Y chromosome as Nowell thought, by Janet Rowley in the 1970s. The formation of the Philadelphia chromosome created a fusion protein from the breakpoint cluster region gene BCR and the tyrosine kinase oncogene ABL that can phosphorylate tyrosine in growth factors constitutively, causing cell proliferation and cancer. This important discovery has assisted in developing more effective treatment regimens for sufferers of chronic myeloid leukaemia by using tyrosine kinase inhibitor drugs such as imatinib and dasitinib, which inhibit activity by binding the ATP site in the kinase domain.

Creator: Aaron Netto

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