What Is the Philadelphia Chromosome?

Philadelphia chromosome: Chromosome pairs 22 and 9 (blue) are affected by what is known as a translocational defect. In a bone marrow stem cell, this defect on chromosome 22 leads to the increased white blood cell count in CML.

The Philadelphia chromosome is a specific finding in the genes of a person’s white blood cells—a finding that has implications for leukemia. It most commonly comes up in reference to “Philadelphia chromosome-positive leukemia.”

More specifically, a leukemia might be called “Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia” (CML) or “Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia” (ALL).

Chromosome Refresher

In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled—many times—around proteins called histones. Unless a cell is dividing in two, chromosomes are not visible within the nucleus—not even under a microscope. That’s because in a non-dividing cell, the DNA is not packed up and away so neatly, since it is being used by the cell at many different locations. However, the DNA that makes up chromosomes becomes very tightly packed during cell division and is then visible under a microscope as a chromosome.

Each chromosome has its own characteristic shape, and the location of specific genes can be found in relation to the shape of a chromosome. When all the genetic material in the cell of a human being gets packaged up, there are 23 pairs of chromosomes, for a total of 46 chromosomes in each cell.

In fact, different species of plants and animals have differing set numbers of chromosomes. A fruit fly, for example, has four pairs of chromosomes, while a rice plant has 12 and a dog, 39.

The Philadelphia Chromosome

The Philadelphia chromosome has a story and a setting, but for practical purposes, it can be defined as an abnormality of chromosome 22 in which part of chromosome 9 is transferred to it.

In other words, a piece of chromosome 9 and a piece of chromosome 22 break off and trade places. When this trade takes place, it causes trouble in the genes – a gene called “bcr-abl” is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.

Bone marrow cells that contain the Philadelphia chromosome are often found in chronic myelogenous leukemia and sometimes found in acute lymphocytic leukemia. Though the Philadelphia chromosome is often thought of in connection with CML and ALL, it can also come up in other contexts, such as “variant Philadelphia translocations,” and “Philadelphia chromosome-negative chronic myeloproliferative disease.”

So you see, the Philadelphia chromosome is a specific genetic change that has become a sort of landmark in medicine, useful for identifying certain cancers by its presence, and other cancers by its absence.

As part of their assessment, doctors will look for the presence of the Philadelphia chromosome to help determine if a patient is affected by particular types of leukemia.

The Philadelphia chromosome is only found in the affected blood cells. Because of the damage to the DNA, the Philadelphia chromosome results in the production of an abnormal enzyme called a tyrosine kinase. Along with other abnormalities, this enzyme causes the cancer cell to grow uncontrollably.

Doctors will look for the presence of this abnormality when they are examining samples from your bone marrow aspiration and biopsy to help make a proper diagnosis.

The identification of the Philadelphia chromosome in the 1960s led to major advancements in the treatment of CML. This laid the foundation for a new era of CML therapy called "tyrosine kinase inhibitors," such as Gleevac (imatinib mesylate) and Sprycel (dasatinib).

More recently, Tasigna (nilotinib) was approved to treat adults who have newly diagnosed Philadelphia chromosome–positive (Ph+) CML in chronic phase. Nilotinib is also considered a tyrosine kinase inhibitor.

Sources

Goldman, J. and Daley, G. (2007). Chronic Myeloid Leukemia. In Melo, J., and Goldman, J. (Eds.) Myeloproliferative Disorders (pp.1-13). New York. Springer.

Sherbenou, D. and Druker, B. "Applying the discovery of the Philadelphia chromosome" The Journal of Clinical Investigation August 2007 117:2067-74.

Adamson PC. Improving the Outcome for Children With Cancer: Development of Targeted New Agents. CA Cancer J Clin. 2015;65(3):212-220.

Nowell PC. Discovery of the Philadelphia chromosome: a personal perspective. Journal of Clinical Investigation. 2007;117(8):2033-2035.

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