Genetics

What is the Philadelphia Chromosome



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The so called Philadelphia chromosome is an abnormal nuclear structure present in most cases of chronic myelogenous leukemia (CML) and to a lesser extent in other types of leukemia, most notably acute lymphocytic leukemia (ALL). The origin of the term Philadelphia chromosome simply reflects the fact that a research team first identified this abnormality in a blood sample from a leukemia patient in Philadelphia, PA.

CML vs. Acute Leukemias

Unlike acute forms of leukemia, in which the cardinal manifestations (fever, weight loss, fatigue) appear abruptly, patients with CML may be asymptomatic for months or even years prior to diagnosis. Even after diagnosis, many patients with chronic forms of leukemia survive 5-10 years or longer.

In approximately 90% of CML patients, the abnormal structure known as the Philadelphia chromosome results from an event known as a chromosomal translocation. Basically, a piece of one chromosome breaks off and attaches itself to a non-homologous chromosome. In CML, a chromosomal translocation occurs between chromosomes 9 and 22. Geneticists abbreviate this event t9:22. The result of this t9:22 translocation is the juxtaposition of the c-abl tyrosine kinase gene on chromosome 9 with the bcr (breakpoint cluster region) on chromosome 22. The product is an abnormal fusion gene that encodes a constitutively active tyrosine kinase called bcr-abl.

The bcr-abl protein is a perpetually active version of a class of proteins called tyrosine kinases that act as cell proliferation signals. The normal versions of these intracellular tyrosine kinases are generally inactivated unless the cell is responding to growth factors or to cytokines that promote cell proliferation. The bcr-abl protein is a different story. It acts like a broken record, continuously telling the cell to copy its DNA and undergo cell division. Consequently, B-lymphocytes (the cell of origin in most leukemias) that undergo a t9:22 translocation begin to proliferate out of control.

Tyrosine kinase inhibitors represent a promising treatment option in CML and other forms of cancer. The first successful drug in this class was imatinib, better known by its trade name Gleevec. This drug binds to and inactivates the bcr-abl protein, significantly extending the survival of patients with CML. Gleevec is also used to treat a relatively rare cancer known as gastrointestinal stromal tumor. A similar drug called lapatinib (Tykerb) has shown promise against certain forms of breast cancer.

Over the years, scientists have discovered that many cancers overexpress growth factor receptors and even secrete their own growth factors. Once these proteins bind to their respective cell surface receptors, they trigger similar intracellular signaling cascades. In other words, similar messenger proteins (mostly tyrosine kinases) transmit a stimulatory signal from outside the cancer cell to various transcription factors and genes within the cell's nucleus that activate mitosis (cell proliferation). Tyrosine kinase inhibitors break this chain of communication, impairing (or ideally halting) the cancer cell's ability to proliferate.

References

1) Kumar, Cotran, Robbins (1999) The Pathological Basis of Disease, pp. 282, 680-681.

2) Lacy, Armstrong, Goldman, and Lance, Drug Information Handbook 19th edition, 2010-2011, pp. 780-781, 878.

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