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Brian Druker
Brian J. Druker (1958 - ) is a physician-scientist at the Oregon Health and Science University. He is the director of OHSU Knight Cancer Institute, JELD-WEN Chair of Leukemia Research, and professor of medicine. In 2009 he won the Lasker Clinical Award and the Meyenburg Cancer Research Prize for his influential work in the development of STI571, commonly known as Gleevec, for the treatment of Chronic Myeloid Leukemia (CML).
http://wn.com/Brian_Druker -
Janet Rowley
Janet Davison Rowley (born April 5, 1925) is an American human geneticist and the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers.
http://wn.com/Janet_Rowley
- BCR gene
- blast crisis
- Brian Druker
- cell cycle
- chemotherapy
- chromosome
- chromosome 22
- CML
- cord blood
- dasatinib
- DNA repair
- enzyme
- fusion gene
- genomic instability
- GIST
- imatinib
- Janet Rowley
- John Kuriyan
- kDa
- nilotinib
- Novartis
- oncogenic
- pediatrics
- protein
- RCC
- Science (journal)
- Sensitivity (tests)
- Specificity (tests)
- sunitinib
- tyrosine
- tyrosine kinase
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- Abl gene
- BCR gene
- blast crisis
- Brian Druker
- cell cycle
- chemotherapy
- chromosome
- chromosome 22
- CML
- cord blood
- dasatinib
- DNA repair
- enzyme
- fusion gene
- genomic instability
- GIST
- imatinib
- Janet Rowley
- John Kuriyan
- kDa
- nilotinib
- Novartis
- oncogenic
- pediatrics
- protein
- RCC
- Science (journal)
- Sensitivity (tests)
- Specificity (tests)
- sunitinib
- tyrosine
- tyrosine kinase
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{{infobox disease | name | Philadelphia chromosome | Image Bcrablmet.jpg | Caption A metaphase cell positive for the bcr/abl rearrangement using FISH | DiseasesDB | ICD10 | ICD9 | ICDO 9875/3 | OMIM | MedlinePlus | eMedicineSubj | eMedicineTopic | MeshID D010677 }} |
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Molecular biology
The exact chromosomal defect in Philadelphia chromosome is a translocation, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 (region q34) to a part of the BCR ("breakpoint cluster region") gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and an truncated chromosome 22 (the Philadelphia chromosome). 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 the oncogenic BCR-ABL gene fusion, located on the shorter derivative 22 chromosome. This gene encodes the Bcr-abl fusion protein. Depending on the precise location of the fusion the molecular weight of the protein can range from 185 to 210 kDa. For this reason bcr-abl is sometimes called p210 or p185. Because the Abl gene expresses a membrane-associated protein, a tyrosine kinase, the BCR-Abl transcript is also translated into a tyrosine kinase, adding a phosphate group to tyrosine. Although the BCR region also expresses serine/threonine kinases, the tyrosine kinase function is very relevant for drug therapy. Tyrosine kinase inhibitors (such as imatinib and sunitinib) are important drugs against a variety of cancers including CML, RCC and GISTs. P210 occurs primarily in CML, and sometimes in Ph-positive acute lymphoblastic leukemia (Ph+ALL), for which the P190 protein is more common. For pediatric Ph+ALL, the impact of this type of fusion gene on prognosis after therapy is unknown since Ph+ALL is rare and to populate statistically relevant studies is difficult.
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 proteins and enzymes, speeding up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.
Nomenclature
Philadelphia chromosome is designated Ph (or Ph') chromosome and the translocation is termed t(9;22)(q34.1;q11.2).
Therapy
Tyrosine kinase inhibitors
In the late 1990s, STI-571 (imatinib, Gleevec/Glivec) was identified by the pharmaceutical company Novartis (then known as Ciba Geigy) in high-throughput screens for tyrosine kinase inhibitors. Subsequent clinical trials led by Dr. Brian J. Druker at Oregon Health & Science University 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". In 2000 John Kuriyan determined the mechanism by which STI-571 inhibits the Abl kinase domain. It was marketed in 2001 by 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. New inhibitors include dasatinib and nilotinib, which are significantly more potent than imatinib and may overcome resistance.Treatment of pediatric Ph+ ALL with a combination of standard chemotherapy and RTK inhibitors may result in remission, but the curative potential is unknown.
Blood or marrow transplants
COG study AALL 0031, which examines the use of Gleevec with standard chemotherapeutic regimens and bone marrow transplant from HLA-matched related donors for high risk ALL (including Ph+ ALL), has concluded, and findings will be published in the near future.A potentially curative, but risky option for pediatric Ph+ ALL or Ph+ CML includes bone marrow transplant or cord blood transplant, but chemotherapy is favored by some for achieving first remission (CR1). For some, bone marrow transplant from a matched sibling donor or a matched, unrelated donor may be favored when remission is obtained.
Cord blood transplant is favored by some when a 10/10 bone marrow match is not available, and cord blood transplant may have some advantages, including a reduced incidence of graft-vs-host disease (GVHD), which is a common and significant complication of transplant. However, transplant with cord blood sometimes requires longer periods of time for engraftment, which may increase the potential for complications due to infection. Regardless of the type of transplant, transplant-related mortality and relapse are possible, and the rates may change as treatment protocols improve. For second remission (CR2), if achieved, both chemotherapy and transplant options are possible, and many physicians prefer transplant.
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 D. Rowley at the University of Chicago identified the mechanism by which the Philadelphia chromosome arises as a translocation.
See also
References
External links
Category:Chromosomal abnormalities
ar:صبغي فيلادلفيا cs:Philadelphský chromozom de:Philadelphia-Chromosom es:Cromosoma Filadelfia fr:Chromosome de Philadelphie hr:Filadelfija kromosom it:Philadelphia (cromosoma) he:כרומוזום פילדלפיה nl:Philadelphiachromosoom ja:フィラデルフィア染色体 pl:Chromosom Philadelphia pt:Cromossomo Filadélfia sv:Philadelphiakromosom te:ఫిలడెల్ఫియా క్రోమోజోము zh:费城染色体
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