Philadelphia chromosome
Encyclopedia
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal
abnormality that is associated with chronic myelogenous leukemia
(CML). It is the result of a reciprocal translocation
between chromosome 9 and 22, and is specifically designated t(9;22)(q34;q11). 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 sufficiently specific 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).
, 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 a 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. Three clinically variants the p190, p210 and p230 isoforms. p190 is generally associated with acute lymphoblastic leukemia
(ALL), while p210 is generally associated with chronic myeloid leukemia but can also be associated with ALL
. p230 is usually associated with chronic neutrophilic leukemia
. Additionally, the p190 isoform can also be expressed as a splice variant
of p210.
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, renal cell carcinoma
(RCC) and gastrointestinal stromal tumor
s (GISTs).
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 blast crisis in CML.
, 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.
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.
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.
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
abnormality that is associated with chronic myelogenous leukemia
Chronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
(CML). It is the result of a reciprocal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
between chromosome 9 and 22, and is specifically designated t(9;22)(q34;q11). 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 sufficiently specific to diagnose CML, since it is also found in acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
(ALL, 25–30% in adult and 2–10% in pediatric
Pediatrics
Pediatrics or paediatrics is the branch of medicine that deals with the medical care of infants, children, and adolescents. A medical practitioner who specializes in this area is known as a pediatrician or paediatrician...
cases) and occasionally in acute myelogenous leukemia (AML).
Molecular biology
The exact chromosomal defect in Philadelphia chromosome is a translocationChromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene
Fusion gene
A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as the result of a translocation, interstitial deletion, or chromosomal inversion...
is created by juxtapositioning the Abl1 gene
Abl gene
V-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9.- Function :...
on chromosome 9 (region q34) to a part of the BCR
BCR gene
The BCR gene is one of the two genes in the bcr-abl complex, which is associated with the Philadelphia chromosome.-Pathology:...
("breakpoint cluster region") gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome). In agreement with the International System for Human Cytogenetic Nomenclature (ISCN), this chromosomal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
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
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
. For this reason bcr-abl is sometimes called p210 or p185. Three clinically variants the p190, p210 and p230 isoforms. p190 is generally associated with acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
(ALL), while p210 is generally associated with chronic myeloid leukemia but can also be associated with ALL
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
. p230 is usually associated with chronic neutrophilic leukemia
Chronic neutrophilic leukemia
Chronic neutrophilic leukemia is a rare myeloproliferative disorder that features a persistent neutrophilia in peripheral blood, myeloid hyperplasia in bone marrow, hepatosplenomegaly, and the absence of the Philadelphia chromosome or a BCR/ABL fusion gene.-Epidemiology:This is a rare disease,...
. Additionally, the p190 isoform can also be expressed as a splice variant
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
of p210.
Because the Abl gene expresses a membrane-associated protein, a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
, the BCR-Abl transcript is also translated into a tyrosine kinase, adding a phosphate group to tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
. Although the BCR region also expresses serine/threonine kinases, the tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
function is very relevant for drug therapy. Tyrosine kinase inhibitors (such as imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
and sunitinib
Sunitinib
Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that was approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor on January 26, 2006...
) are important drugs against a variety of cancers including CML, renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
(RCC) and gastrointestinal stromal tumor
Gastrointestinal stromal tumor
A gastrointestinal stromal tumor is one of the most common mesenchymal tumors of the gastrointestinal tract...
s (GISTs).
The fused BCR-Abl protein interacts with the interleukin-3 receptor
Interleukin-3 receptor
The interleukin-3 receptor is a molecule found on cells which helps transmit the signal of interleukin-3, a soluble cytokine important in the immune system....
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
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
-controlling protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s and enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s, speeding up cell division. Moreover, it inhibits DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
, 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).Tyrosine kinase inhibitors
In the late 1990s, STI-571 (imatinibImatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
, Gleevec/Glivec) was identified by the pharmaceutical company Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
(then known as Ciba Geigy) in high-throughput screens for tyrosine kinase inhibitors
Protein kinase inhibitor
A protein kinase inhibitor is a type of enzyme inhibitor that specifically blocks the action of one or more protein kinases. Hence, they can be subdivided or characterised by the amino acids whose phosphorylation is inhibited:...
. Subsequent clinical trials led by Dr. Brian J. Druker
Brian Druker
Brian J. Druker is a physician-scientist at the Oregon Health & Science University. He is the director of OHSU Knight Cancer Institute, JELD-WEN Chair of Leukemia Research, and professor of medicine...
at Oregon Health & Science University
Oregon Health & Science University
Oregon Health & Science University is a public university in Oregon with a main campus, including two hospitals, in Portland and a smaller campus in Hillsboro...
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
John Kuriyan
John Kuriyan is currently Chancellor's Professor at the University of California Berkeley in the departments of Molecular and Cell Biology and Chemistry. He is also a Faculty Scientist in Berkeley Lab's Physical Biosciences Division, a Howard Hughes Medical Institute investigator, and a member of...
determined the mechanism by which STI-571 inhibits the Abl kinase domain.
It was marketed in 2001 by Novartis as imatinib mesylate
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
(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
Dasatinib
Dasatinib, previously known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral multi- BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia after imatinib treatment...
and nilotinib
Nilotinib
Nilotinib , in the form of the hydrochloride monohydrate salt, is a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia.-Uses:...
, which are significantly more potent than imatinib and may overcome resistance.
Treatment of pediatric Ph+ ALL with a combination of standard chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and RTK
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
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 transplantBone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
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
Cord blood
Umbilical cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells which can be used to treat hematopoietic and genetic disorders.-Collection:...
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
Cord blood
Umbilical cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells which can be used to treat hematopoietic and genetic disorders.-Collection:...
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 MedicineUniversity of Pennsylvania School of Medicine
The Perelman School of Medicine , formerly the University of Pennsylvania School of Medicine, was founded in 1765, making it the oldest American medical school. As part of the University of Pennsylvania, it is located in the University City section of Philadelphia, Pennsylvania. It is widely...
and David Hungerford from the Fox Chase Cancer Center
Fox Chase Cancer Center
The Fox Chase Cancer Center is a National Cancer Institute-designated Comprehensive Cancer Center research facility and hospital located in the Fox Chase section of Philadelphia, Pennsylvania, United States. The main facilities of the center are located on property adjoining Burholme Park...
's Institute for Cancer Research and was therefore named after the city in which both facilities are located.
In 1973, Janet D. Rowley
Janet Rowley
Janet Davison Rowley is an American human geneticist and the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers....
at the University of Chicago
University of Chicago
The University of Chicago is a private research university in Chicago, Illinois, USA. It was founded by the American Baptist Education Society with a donation from oil magnate and philanthropist John D. Rockefeller and incorporated in 1890...
identified the mechanism by which the Philadelphia chromosome arises as a translocation.
See also
- Refer to the article on Chronic myelogenous leukemiaChronic myelogenous leukemiaChronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
for more details on diagnosis and treatment.