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The Philadelphia chromosome arises as a result of a spontaneous mutation that occurs randomly. The discovery of the Philadelphia chromosome was the first evidence in the history of medicine that genetics was linked to the development of cancer. What is the Philadelphia chromosome? What diseases can it accompany? What are the effects of the Philadelphia chromosome?

Philadelphia chromosomeis a disorder in the organization of the genetic material of a human, associated with a predisposition to the development of blood cancers - leukemias. In 1959, two American scientists working in Philadelphia were studying the blood cells of patients suffering from chronic myeloid leukemia (CML). While conducting their experiments, they noticed the presence of abnormally constructed, shortened chromosomes. This dissimilarity, typical of some hematological cancers, was later called the Philadelphia chromosome.

How is the human genetic material organized? What are chromosomes?

Before we deal with the detailed description of the Philadelphia chromosome, it is worth briefly introducing the correct organization of the human genetic material.

Each cell in our body has a genetic code - a double strand of DNA, which contains all the information necessary for the proper development and activity of this cell. It is not difficult to guess that the amount of this information is enormous, which makes the DNA strand unimaginably long. DNA in this form would not have a chance to fit into the cell nucleus - so it has to be specially compressed and packed. Such tightly twisted "bundles" of DNA are called chromosomes.

Correctly, each cell contains a set of 23 pairs of chromosomes for a total of 46 chromosomes. In each pair, one chromosome is inherited from the mother and the other from the father. The last pair of chromosomes is called the sex chromosomes - these are the XX chromosomes in the female and the XY chromosomes in the male.

Each chromosome has a whole lot of genes that, depending on the needs of the organism, can be activated or deactivated at a given moment. Which genes are in the activated state translates into the current activity of the cell - whether it is multiplying at the moment, is it producing proteins, or is it resting.

human DNA, packed in chromosomes,is in constant use - it constantly controls the activity of the cell. During the daily processes of the cell nucleus, DNA can be changed and damaged. Such changes in the genetic material are called mutations.

Mutationscan have different sizes and consequences. Some minimal-range mutations often have no effect whatsoever on cell life. Large mutations that alter the structure of entire chromosomes are calledstructural chromosomal aberrations .

The cell has a whole lot of defense systems, whose task is to constantly remove emerging mutations. Unfortunately, due to some factors (such as aging or environmental factors such as ionizing radiation), DNA repair systems can become ineffective. In such a situation, the mutation becomes permanent and may lead to the development of a genetic disease.

What is a Philadelphia chromosome?

The Philadelphia chromosome is an example of a chromosome structure disorder. The mutualtranslocationis responsible for its formation, i.e. a type of mutation in which two chromosomes break and exchange fragments of their arms with each other.

The Philadelphia chromosome is formed when the exchange takes place between chromosome 9 and 22. The reciprocal translocation leads to an elongation of chromosome 9 and a shortening of chromosome 22.

As a result of cytogenetic examination, the presence of the Philadelphia chromosome in cells is schematically marked t (9; 22) (q34; q11) - this abbreviation means the exchange of specific fragments of long arms (q) between chromosomes 9 and 22.

Why is the Philadelphia chromosome formed?

Although the Philadelphia chromosome is a genetic disorder, it is not hereditary. The Philadelphia chromosome is formed as a result of a spontaneous mutation that occurs randomly - it is not known why it occurs in some people and not in others.

The only environmental factor proven to be associated with an increased risk of Philadelphia chromosome formation (as well as other genome changes) is exposure to ionizing radiation.

Philadelphia chromosome and neoplastic processes

Now that we know how the Philadelphia chromosome is formed, it is worth asking: what are the effects of its presence in the cell? Unfortunately, the replacement of chromosome fragments, in addition to changing their appearance, carries much more serious consequences.

It should be noted here that specific fragments of genetic material are transferred between chromosomes. In the case of the Philadelphia chromosome, the BCR gene is transferred from chromosome 22,into the region of the ABL gene, located on the 9 chromosome. In this way, the so-called fusion gene is created, i.e. created as a result of joining two genes.

The ABL gene belongs to a unique group of genes called proto-oncogenes. Under normal conditions, its function remains under constant supervision - the gene is constantly "watched over" so that it does not become over-activated. The combination of the BCR-ABL genes causes a loss of this control. ABL then becomes an oncogene - that is, a gene that leads to cancer.

The newly formed BCR-ABL gene leads to the continuous production of a protein that has a huge impact on the activity of the cell. This protein leads to continuous, rapid multiplication of cells that are out of any control. Additionally, these cells stop dying naturally and become "immortal".

We associate this description of cell behavior with cancer. And rightly so, because the Philadelphia chromosome is one of the genetically determined mechanisms of leukemia development.

The formation of leukemia is associated with the uncontrolled multiplication of white blood cells. The Philadelphia chromosome, present in the precursor cells in the bone marrow, produces enormous amounts of leukocytes, which then pass into the bloodstream and can invade various organs.

The most common type of leukemia associated with the Philadelphia chromosome is chronic myeloid leukemia (CML) - the Philadelphia chromosome is found in more than 90% of patients with the disease.

The mere presence of the Philadelphia chromosome is not the only basis for qualifying leukemia as CML, as it can also occur in other types of leukemia. These include, among others:

  • acute lymphoblastic leukemia (ALL)
  • (less frequently) acute myeloid leukemia (AML)
  • mixed-type leukemias

The role of the Philadelphia chromosome in the diagnosis and treatment of leukemias

The discovery of the Philadelphia chromosome has opened up many possibilities in the diagnosis and therapy of leukemias. The diagnosis and classification of the type of leukemia is currently based on several types of research:

  • peripheral blood count with smear
  • and bone marrow cell examination

Thanks to the progress in the field of cytogenetic diagnostics (the possibility of viewing cells under a microscope with very high magnification) and molecular diagnostics (direct DNA analysis), in the case of suspected leukemia, both the Philadelphia chromosome and the BCR-ABL fusion gene tests are performed. Confirmation of their presence is the basis for the diagnosis of chronic myeloid leukemia (CML).

Philadelphia chromosome as mentionedearlier, it can also occur in other types of leukemia. It is then a useful factor in classifying and influencing the choice of therapy - the specific type of leukemia is defined as:

  • Ph (Philadelphia) -dodatni
  • or Ph-negative

If the Philadelphia chromosome is present, the patient is usually eligible for targeted therapy with imatinib and its derivatives (see below).

In addition to the breakthrough in the discovery of the relationship of chromosome mutations with the development of hematological cancers, research on the Philadelphia chromosome and the BCR-ABL gene resulted in the invention of modern, targeted methods of anti-cancer therapy.

Thanks to the discovery of a protein - a product of the BCR-ABL gene, which causes continuous, uncontrolled multiplication of cells, new groups of drugs have been developed. This protein is called tyrosine kinase, and drugs that inhibit its activity are called tyrosine kinase inhibitors.

Imatinib was the first tyrosine kinase blocker to be introduced to the pharmaceutical market. The use of this drug in the treatment of chronic myeloid leukemia was a turning point - the drug is highly effective and significantly improves patients' prognosis. Currently, there are more preparations available on the market with a mechanism of action similar to that of Imatinib. They are used, inter alia, in those patients in whom Imatinib did not provide the expected response.

Philadelphia chromosome cytogenetics is also useful in monitoring the course of the disease and assessing response to treatment. The decrease in the number of cells with the Philadelphia chromosome in the bone marrow indicates a positive response to the therapy.

About the authorKrzysztof BialaziteA medical student at Collegium Medicum in Krakow, slowly entering the world of constant challenges of the doctor's work. She is particularly interested in gynecology and obstetrics, paediatrics and lifestyle medicine. A lover of foreign languages, travel and mountain hiking.

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Category:

Oncology