Philadelphia chromosome
The Philadelphia chromosome ( Ph1 outdated ) is a shortened chromosome 22, which is found in some human leukemias. It is caused by a chromosomal translocation between chromosomes 9 and 22, the notation is the cytogenetic translocations: t (9, 22 ) ( q34, q11 ).
The Philadelphia chromosome was first in 1960 by Peter Nowell and David Hungerford in Philadelphia in leukemia cells of a patient with chronic myelogenous leukemia ( CML) described and got its name from the place of discovery. It was the first identified chromosomal abnormalities, which could be associated with the development of cancer. More than 95 percent of patients with CML, the change is detectable. Later it was discovered that it is also found in a subset of patients with acute lymphocytic leukemia (ALL ) (about 4% of cases in children and 25 % in adults ), very rarely, in acute myeloid leukemia (AML; at less than one percent of the cases).
- 4.1 Notes and references
- 4.2 Literature
- 4.3 External links
Emergence and consequences
Translocation
The chromosome change takes place in a stem cell of the blood in the bone marrow. In this case, the chromosome 9 breaks in the area q34.1 (q designate the long chromosome arm, 34.1 's position in a ) and the chromosome 22 q11.2. The break point lies on both chromosomes in a range of genes, ABL (or ABL1, Oncogene for Abelson Murine Leukemia Viral homolog 1) on chromosome 9 and the BCR gene ( " breakpoint cluster region "; named due to frequent breakages in this gene ) on chromosome 22
Wherein translocation of the 5 'portion of the 3' part of the BCR to the ABL gene is linked. There are different possible breakpoints in the BCR gene, but only one break point in the ABL gene, so that different sized fusion genes arise in which the proportion of the ABL gene is always the same, the size of the BCR- proportion but varied. In this way leads to the formation of the BCR-ABL fusion genes on chromosome 22 and ABL - BCR on chromosome 9, which is designated in its extended form as now 9q . The so-called philadelphia -positive leukemias (mostly CML) is the chromosomal translocation at cytogenetic investigation as shortened chromosome 22, just as described here Philadelphia chromosome visible. Via a specific polymerase chain reaction, the gene may be detected.
The cause of these chromosomal abnormalities is not known in most cases, or not detectable. In very few cases is the cause a radiation accident ( ionizing radiation ) or benzene into consideration.
Gene
By the mutual (reciprocal ) translocation t (9, 22 ) ( q34, q11 ), and the new fusion genes leads to a modified gene on both chromosomes. The newly formed on chromosome 22 BCR- ABL gene is transcribed in the cell, thereby producing a new protein BCR -ABL gene product, a fusion protein. Translation of the resulting mRNA resulting in the synthesis of the modified protein. Originally transcribed by the ABL gene is a tyrosine kinase enzyme / G -protein Ras and plays an important role in cell growth regulation. The fusion protein consists of the amino terminus of the BCR protein and equipped with a carboxy kinase domain of ABL. Thus, the tyrosine kinase activity is activated permanently under the influence of the BCR region and the affected cell multiplies uncontrollably ( lack of apoptosis). This development, the cell is a tumor cell.
The specific mechanism, such as the new fusion gene leads to uncontrolled proliferation is not yet fully elucidated. Normally, the ABL gene has two exons introductory 1a and 1b which can be used alternatively in the transcription. The selection will take place in splicing with exon 2, which has a so-called splice acceptor site and here can either 1a or 1b dock. In the translocation of the exon 1 is replaced with the fragment of the BCR is also accepted by the exon 2, and the gene is transcribed and thus added together with the exon 2 to 11 of the ABL.
Oncogenic effect
See main article Chronic myeloid leukemia and acute lymphoblastic leukemia
The altered tyrosine kinase activity of the ABL gene under the influence of BCR- region, the affected cell increases uncontrollably and becomes a tumor cell. As a pluripotent stem cell, it produces different cell types, which also contain the modified chromosome. Thus, all derived from this stem cell cells containing the modified chromosomal pair 9 and 22 and thus the Philadelphia chromosome. To a pathological effect, however, it is only in the leukemic changes in white blood cells.
Since ABL as well as other versions of the ABL gene ( for v -ABL see below) by a change in the opening sequence to an oncogene, it is called a proto- oncogene. Similar to other translocations leading to tumor diseases here arises an oncogene by fusion of two normal genes.
The fusion protein binds to several other proteins, including about the kinase regulatory protein CRK ( CT10 regulator of kinase), which Phosphatidylinsitol -3'- kinase and GRB-2/SOS-1. By binding to the latter is the activation of the ras gene, which plays a central role in the control of cell growth and cell proliferation, increased. RAS mutations in turn are regarded as central triggers of various tumors and may play a central role in the oncogenic effect of the BCR -ABL gene.
Variations and additional chromosomal changes
In detail, the translocations that lead to chronic myeloid leukemia ( CML) and acute lymphoblastic leukemia ( ALL), at the position of the break in the BCR gene of chromosome 22 and thus also in the length of the later resulting BCR -ABL differ gene product. The break in the chromosome 9 is always in the same intron. The breakpoint in chromosome 22 varies, however. In the BCR- Region three break points are described so far. They are m- BCR ( minor), M - BCR (Major) and μ - BCR (micro) called. The break point m- BCR is the most 5 '. The resulting fusion protein is therefore with about 190 kDa smallest. The break point M- bcr is farther 3 'and results in a fusion protein of 210 kDa size. The breakpoint μ - BCR is the furthest 3 'and leads to the largest BCR -ABL fusion protein of 230 kDa.
Fusion genes, leukaemias and Cytogenetic Status
In the literature, three different BCR -abl fusion genes are thus described. The Ph chromosome is found not only in CML but also in about 20 percent of the cases studied in the ALL of the adults in five percent of the cases studied in the ALL of the child and in about two percent of the cases with AML. In addition, have some of the examined patients with CML or an adult form of ALL no Ph chromosome, but it can be a fusion gene are detected. There is also a small number of patients with CML who have neither a Ph chromosome, nor express a fusion gene.
Chronic myeloid leukemia
90 to 95 percent of patients with chronic myelogenous leukemia (CML ) have a Ph- chromosome. About 99 percent of all patients with CML express the 210 - kD fusion. About five percent of patients with CML are Ph- negative, of these, the 210 - kD fusion product is in nearly 100 percent of the cases studied also expressed. Thus, in the CML is usually located approximately in the center of the BCR gene called BCR major region affected, which is about 5.8 kb of a total of 90 kb gene. The resulting gene product has a mass of 210 kDa ( P210 ) compared to the mass of 145 kDa of the original ABL protein, 140 kDa and 70 kDa ABL attributable to BCR.
Acute lymphoblastic leukemia in adults
In approximately 20 percent of adult patients with ALL can be found with cytogenetics methods, a Ph chromosome. Here, the bcr gene breaks in 20-50 percent of cases within the first intron (minor - bcr region) and the gene product of the fusion gene is only 185 kDa long, of which account for 45 kDa BCR. In 50-80 percent of cases of M- BCR breakpoint is hit. This leads to the usually occurring in CML and 210 kD fusion protein. About 10 percent of adult patients with ALL are Ph- negative but expressing a BCR -abl fusion gene. In these rare cases, the 190 kDa and 210 kDa form are often found about the same.
Acute lymphoblastic leukemia of childhood
When ALL of the child can be found in five percent of the cases studied a Ph chromosome. These children with Ph -positive ALL express it in 10 percent of the cases studied, the 210 kDa fusion protein and in 90 percent of the 190 kDa protein. The constellation of a ph -negative childhood ALL with proof of Bcr -Abl fusion protein is not known.
Acute myeloid leukemia
About two percent of the cases studied from patients with AML show a cytogenetically Ph chromosome. In these rare cases, the fusion proteins p210 and p190 come before about the same frequency. In very rare cases one finds patients with Ph -negative AML expressing a Bcr-Abl fusion gene.
Other findings
Patients who have a Philadelphia chromosome, in the affected cells have also often further modified and multiplied in the chromosomes, thus developing so-called somatic aneuploidies. It could be determined in 17 clinical trials of 67 CML patients at nearly 50 percent of those examined (33 ), an additional Philadelphia chromosome and 28 trisomy of the long arm of the chromosome. In addition to these two forms other aneuploidies of the cells occurred.
Comparable oncogenes
Comparable to the oncogenic effect of the genetic modification in the Philadelphia chromosome, the effect of the Abelson murine leukemia virus, a retrovirus, the leukemia caused by B- lymphocytes from mice. Again, a ABL gene (v -Abl ) with another gene, in this case, the gag gene of the virus changes, and an increased tyrosine kinase activity is stimulated. Due to the similarity of the genetic modification in accordance with diseased mice are used as model organisms for the development of preparations against the oncogenic effect of chromosomal abnormalities in pharmaceutical research as well as for basic research.
History of Research
The Philadelphia chromosome was described in 1960 by Peter Nowell of the University of Pennsylvania School of Medicine and David Hungerford from the Fox Chase Cancer Center 's Institute for Cancer Research is the first constant occurring chromosomal alteration in tumor cells, and on patients with chronic myeloid leukemia. They found a very short chromosome, which they held only for the Y chromosome, in the blood samples of two patients. Later it turned out that it was the shortened chromosome 22, which according to the place of its discovery as the Philadelphia chromosome ( Ph1 abbreviated ) was named. In a recent report, PC Nowell describes his personal memories to the discovery of the Philadelphia chromosome ..
In 1972, Janet Rowley showed that this chromosome is created by an exchange of genetic material between the long arms of chromosome 9 and chromosome 22.
In the years 1983 and 1984 it was discovered that there are at the chromosome break points, two genes ( ABL and BCR), which are fused together by the chromosomal translocation.
The pharmacological research endeavored subsequently to block the oncogenic effect of the modified gene. With the help of imatinib, a process developed in the 1980s inhibitor of the BCR -ABL tyrosine kinase, it is now possible to achieve in CML prolonged remissions.