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Encyclopedia > Philadelphia chromosome

Philadelphia chromosome or Philadelphia translocation is a specific genetic, chromosomal abnormality that is associated with chronic myelogenous leukemia (CML) and involves an exchange of material between chromosomes 9 and 22. 95% of patients with CML show this abnormality; the remainder harbour either a cryptic translocation that is invisible on G-banded chromosome preparations or a variant translocation involving another chromosome or chromosomes as well as chromosomes 9 and 22. 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). Genetics (from the Greek genno γεννώ= give birth) is the science of genes, heredity, and the variation of organisms. ... Figure 1: Chromosome. ... Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. ... Acute lymphoblastic leukaemia (ALL), also known as acute lymphocytic leukaemia, is a cancer of the white blood cells, characterised by the overproduction and continuous multiplication of malignant and immature white blood cells (referred to as lymphoblasts) in the bone marrow. ... Pediatrics (also spelled paediatrics or pædiatrics) is the branch of medicine that deals with the medical care of infants, children, and adolescents. ... Acute myelogenous leukemia (AML), also known as acute myeloid leukemia, is a cancer of the myeloid line of blood cells. ...

Contents


Molecular biology

A metaphase cell positive for the bcr/abl rearrangement using FISH
A metaphase cell positive for the bcr/abl rearrangement using FISH

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. FISH image of bcr/abl positive rearranged metaphase File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... FISH image of bcr/abl positive rearranged metaphase File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... FISH (Fluorescent in situ hybridization) is a cytogenetic technique which can be used to detect and localize DNA sequences on chromosomes. ... Chromosomal translocation of the 4th and 20th chromosome. ... Figure 1: Chromosome. ... The abl gene is accociated with chronic myelogenous leukemia. ...


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 Kampfgruppen der Arbeiterklasse (German: Combat Groups of the Working Class) was a paramilitary organisation in East Germany, founded in 1953 and abolished in 1990. ... Tyrosine (from the Greek tyros, meaning cheese, as it was first discovered in cheese), 4-hydroxyphenylalanine, or 2-amino-3(4-hydroxyphenyl)-propanoic acid, is one of the 20 amino acids that are used by cells to synthesize proteins. ... Tyrosine kinases are a subclass of protein kinase, see there for the principles of protein phosphorylation A tyrosine kinase (EC 2. ...


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 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. Interleukins are a group of cytokines that are expressed by white blood cells (leukocytes, hence the -leukin) as a means of communication (inter-). The function of the immune system depends in a large part on interleukins, and rare deficiencies of a number of them have been described, all featuring autoimmune... The cell cycle, or cell division cycle, is the cycle of events in a eukaryotic cell from one cell division to the next. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Ribbon diagram of the enzyme TIM. TIM is catalytically perfect, meaning its conversion rate is limited, or nearly limited to its substrate diffusion rate. ... DNA damage resulting in multiple broken chromosomes DNA repair is a process constantly operating in cells; it is essential to survival because it protects the genome from damage and harmful mutations. ... Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. ...


Image:Philadelphia_transformation.jpg Made by me for an essay File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ...


Nomenclature

Philadelphia chromosome is designated Ph (or Ph') chromosome and the translocation is termed t(9;22)(q34;q11).


Therapy

In the late 1990s, STI-571 (Imatinib, Gleevec) 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 1990s decade refers to the years from 1990 to 1999, inclusive. ... 2001: A Space Odyssey. ... A pharmaceutical company (or drug company) is a company licensed to discover, develop, market and distribute drugs. ... Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland. ... Imatinib is a drug used to treat certain types of cancer. ...


History

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 Fox Chase Cancer Center's Institute for Cancer Research and therefore named after the city in which both facilities are located. 1960 (MCMLX) was a leap year starting on Friday (the link is to a full 1960 calendar). ... Philadelphia is a village located in Jefferson County, New York. ... The University of Pennsylvanias School of Medicine, presently located in the University City section of Philadelphia, Pennsylvania, was the countrys first school of medicine, founded at the College of Philadelphia, as the University was then called. ... The Fox Chase Cancer Center, is a Research center and hospital located in The Northeast section of Philadelphia, Pennsylvania, United States. ...


In 1973, Janet D. Rowley at the University of Chicago identified translocation as a source of the abnormality. 1973 (MCMLXXIII) was a common year starting on Monday (the link is to a full 1973 calendar). ... Dr Janet Davison Rowley (born 1925) is an American human geneticist, she was the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers. ... The University of Chicago is a private university principally located in the Hyde Park neighborhood of Chicago, Illinois, founded in 1890 and opened in 1892. ...


See also

Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. ...

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 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 608232, OMIM 151410 (BCR), OMIM 189980 (ABL)

  Results from FactBites:
 
Philadelphia chromosome - Wikipedia, the free encyclopedia (590 words)
Philadelphia chromosome or Philadelphia translocation is a specific genetic, chromosomal abnormality that is associated with chronic myelogenous leukemia (CML) and involves an exchange of material between chromosomes 9 and 22.
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 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).
  More results at FactBites »

 
 

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