View source for Philadelphia chromosome

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  Image          = Bcrablmet.jpg|
  Caption        = A metaphase cell positive for the bcr/abl rearrangement using [[Fluorescent in situ hybridization|FISH]] |
  DiseasesDB     = |
  ICD10          = {{ICD10|C|92|1|c|81}} |
  ICD9           = {{ICD9|205.1}} |
  ICDO           = 9875/3 |
  OMIM           = |
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  eMedicineSubj  = |
  eMedicineTopic = |
  MeshID         = D010677 |
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==Overview==
'''Philadelphia chromosome''' or '''Philadelphia translocation''' is a specific [[chromosome|chromosomal]] abnormality that is associated with [[chronic myelogenous leukemia]] (CML).  It is due to a reciprocal [[chromosomal translocation|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&ndash;30% in adult and 2&ndash;10% in [[pediatrics|pediatric]] cases) and occasionally in [[acute myelogenous leukemia]] (AML).

==Molecular biology==

The exact chromosomal defect in Philadelphia chromosome is [[Chromosomal translocation|translocation]]. Parts of two chromosomes, 9 and 22, swap places. The result is that part of the ''[[BCR gene|BCR]]'' ("breakpoint cluster region") gene from [[chromosome]] 22 (region q11) is fused with part of the ''[[Abl gene|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 [[protein]]s and [[enzyme]]s, speeding up cell division. Moreover, it inhibits [[DNA repair]], causing genomic instability and potentially causing the feared [[Chronic myelogenous leukemia#Blast crisis|blast crisis]] in CML.
[[Image:Philadelphia_chromosome.jpg]]

== Nomenclature ==
Philadelphia chromosome is designated <b>Ph (or Ph') chromosome</b> and the translocation is termed '''t(9;22)(q34.1;q11.2)'''.

==Therapy==
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|imatinib mesylate]] (Gleevec&reg; in the US, Glivec&reg; 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.

==History==
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 Rowley|Janet D. Rowley]] at the [[University of Chicago]] identified the mechanism by which the Philadelphia chromosome arises as a translocation.

== See also ==
*Refer to the article on [[Chronic myelogenous leukemia]] for more details on diagnosis and treatment.
*[[Chromosomal translocation]]

== References ==
<small> <div style="-moz-column-count:2; column-count:2;">
* Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. "Philadelphia Chromosome-positive leukemias: from basic mechanisms to molecular therapeutics." ''Ann Intern Med'' 2003;138:819&ndash;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&ndash;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." <i>Cell</i> [[1984]];37(3):1035&ndash;42. PMID 6204766 
* {{OMIM|608232}}, {{OMIM|151410}} (BCR), {{OMIM|189980}} (ABL)
</div> </small>

{{Chromosomal abnormalities}}
{{Hematological malignancy histology}}
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[[Category:Mature chapter]]
[[Category:Disease state]]
[[Category:Genetic disorders]]
[[Category:Oncology]]
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[[ar:كروموسوم فيلادلفيا]]
[[de:Philadelphia-Chromosom]]
[[es:Cromosoma Filadelfia]]
[[nl:Philadelphiachromosoom]]
[[pl:Chromosom Philadelphia]]
[[pt:Cromossomo Filadélfia]]
[[sv:Philadelphiakromosom]]
[[ja:フィラデルフィア染色体]]

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