Philadelphia chromosome 526659 221991728 2008-06-27T01:06:51Z AlnoktaBOT 3096998 robot Modifying: [[ar:صبغي فيلادلفيا]] {{Infobox_Disease | Name = Philadelphia chromosome | 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 = | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = D010677 | }} '''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 [[Sensitivity (tests)|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 sufficiently [[Specificity (tests)|specific]] to diagnose CML, since it is also found in [[acute lymphoblastic leukemia]] (ALL, 25–30% in adult and 2–10% 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-3 receptor]] beta(c) 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 '''Ph (or Ph') chromosome''' 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 [[Protein kinase inhibitor|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 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. ==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]] == Sources == * 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 (journal)|Science]]'' 1960;132:1497. * Rowley JD. "A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]". ''[[Nature (journal)|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 * {{OMIM|608232}}, {{OMIM|151410}} (BCR), {{OMIM|189980}} (ABL) ==External links== * {{MeshName|Philadelphia+chromosome}} {{Chromosomal abnormalities}} {{Hematological malignancy histology}} [[Category:Genetic disorders]] [[ar:صبغي فيلادلفيا]] [[de:Philadelphia-Chromosom]] [[es:Cromosoma Filadelfia]] [[hr:Filadelfija kromosom]] [[nl:Philadelphiachromosoom]] [[ja:フィラデルフィア染色体]] [[pl:Chromosom Philadelphia]] [[pt:Cromossomo Filadélfia]] [[sv:Philadelphiakromosom]]