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Philadelphia chromosome or Philadelphia translocation is a specific genetic, chromosomal abnormality that is associated with chronic myelogenous leukemia (CML). 95% of patients with CML show this abnormality; a remaining 2-3% harbor a very similar abnormality. The complete absence of the Philadelphia chromosome actually indicates a poor prognosis. The Ph chromosome is also found in acute lymphoblastic leukemia (ALL, 25-30% in adult and 2-10% in pediatric cases) and occasionally in acute myelogenous leukemia (AML).
The exact chromosomal defect in Philadelphia chromosome is translocation. Parts of two chromosomes, 9 and 22, swap places. The result is that part of the BCR ("breakpoint cluster region") gene from chromosome 22 (region q11) is fused with part of the ABL gene on chromosome 9 (region q34). Abl stands for "Abelson", the name of a leukemia virus which carries a similar protein.
The result of the translocation is a protein of p210 or sometimes p185 weight (p is a weight fraction of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (tyrosine kinase) the bcr-abl fusion gene is also a tyrosine kinase. (Although the bcr region is also a serine/threonine kinase, the tyrosine kinase function is very relevant for therapy, as will be shown.)
The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The bcr-abl transcript is continuously active, i.e. it does not require activation by other cellular messenging proteins. In turn, bcr-abl activates a number of cell cycle-controlling proteins and enzymes, speeding up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.
Philadelphia chromosome is designated Ph (or Ph') chromosome and the translocation is termed t(9;22)(q34;q11).
In the late 1990s, Dr Brian J. Druker identified the compound then known as STI-571 as having an inhibitory effect on bcr-abl. Although it did not eradicate CML cells, it did greatly limit the growth of the tumor clone and decreased the risk of the feared "blast crisis". It was marketed in 2001 by the pharmaceutical company Novartis as imatinib mesylate (Gleevec® in the US, Glivec® in Europe). Other pharmacological inhibitors are being developed.
The phenomenon was first discovered and described in 1960 by scientists from Philadelphia, Peter Nowell from University of Pennsylvania School of Medicine and David Hungerford from the Institute for Cancer Research and therefore named after the city.
- Refer to the article on Chronic myelogenous leukemia for more details on diagnosis and treatment.
- Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. Phildelphia Chromosome-positve leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003;138:819-30. PMID 12755554.
- Nowell P, Hungerford D. A minute chromosome in chronic granulocytic leukemia. Science 1960;132:1497.
- Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature 1973;243:290-3. PMID 4126434.
- , OMIM 151410 (BCR), OMIM 189980 (ABL)
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