|A metaphase cell positive for the bcr/abl rearrangement using FISH|
Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML). It is due to a reciprocal translocation designated as t(9;22)(q34;q11), which means an exchange of genetic material between region q34 of chromosome 9 and region q11 of chromosome 22. The presence of this translocation is a highly sensitive test for CML, since 95% of people with CML have this abnormality (The remainder have either a cryptic translocation that is invisible on G-banded chromosome preparations, or a variant translocation involving another chromosome or chromosomes as well as the long arm of chromosomes 9 and 22). However, the presence of the Philadelphia (Ph) chromosome is not sufficient to diagnose CML, since it 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). In agreement with the International System for Human Cytogenetic Nomenclature (ISCN), this chromosomal translocation is designated as t(9;22)(q34;q11). 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(p simply stands for "protein"; the numbers represent the apparent molecular weight of the mutant proteins in kDa). The fused "bcr-abl" gene is located on the resulting, shorter chromosome 22. 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 constitutively active, i.e. it does not require activation by other cellular messaging 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)(q34.1;q11.2).
In the late 1990s, STI-571 (imatinib, Gleevec/Glivec) was identified by Novartis pharmaceuticals in high-throughput screens for tyrosine kinase inhibitors. Subsequent clinical trials led by Dr Brian J. Druker in collaboration with Dr. Charles Sawyers and Dr. Moshe Talpaz demonstrated that STI-571 inhibits proliferation of BCR-ABL-expressing hematopoietic cells. 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, which are more potent and/or are active against the emerging Gleevec/Glivec resistant BCR-abl clones in treated patients. The majority of these resistant clones are point-mutations in the kinase of BCR-abl.
The Philadelphia chromosome was first discovered and described in 1960 by Peter Nowell from University of Pennsylvania School of Medicine and David Hungerford from the Fox Chase Cancer Center's Institute for Cancer Research and was therefore named after the city in which both facilities are located.
In 1973, Janet D. Rowley at the University of Chicago identified the mechanism by which the Philadelphia chromosome arises as a translocation.
- Refer to the article on Chronic myelogenous leukemia for more details on diagnosis and treatment.
- Chromosomal translocation
- Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. "Philadelphia Chromosome-positive 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.
- Konopka JB, Watanabe SM, Witte ON. "An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity." Cell 1984;37(3):1035–42. PMID 6204766
- Online Mendelian Inheritance in Man (OMIM) 608232, Online Mendelian Inheritance in Man (OMIM) 151410 (BCR), Online Mendelian Inheritance in Man (OMIM) 189980 (ABL)
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