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CML and the Philadelphia Chromosome: 50 Years of Progress


How this accidental discovery led to a breakthrough in cancer research and the treatment of chronic myelogenous leukemia

By Natalie Castro


In 1959, when a young pathologist named Peter Nowell accidentally used tap water instead of distilled water to rinse cultured blood cells taken from patients with chronic myelogenous leukemia (CML), a type of slow-progressing cancer of the white blood cells, he noticed a subtle abnormality in one of the chromosomes. After teaming up with the late David Hungerford, PhD, of the Fox Chase Cancer Center, who was then a graduate fellow studying human chromosomes at the Institute for Cancer Research in Philadelphia, the two detected a shortened chromosome number 22 and named it the Philadelphia chromosome after the city where it was discovered. In 1960, the Journal of the National Cancer Institute published Dr. Nowell and Dr. Hungerford's evidence linking the abnormality with CML, which suggested for the first time in history that cancer could be caused by genetic mutations.

What was a mistake is undoubtedly regarded as a scientific breakthrough in cancer research. At the time, the consensus among scientists was that cancer was caused by a virus or by extreme exposure to radiation. "It was the first real evidence that a genetic mutation could cause a cell to grow abnormally," said Dr. Nowell, who added that viruses can still play a role in cancer diagnosis.

The discovery of the Philadelphia chromosome prompted researchers to further study the implications of genetic abnormalities. In 1973, Janet D. Rowley, MD, now a professor of hematology and oncology at the University of Chicago, discovered that the shortened chromosome 22 was a result of a translocation, or rearrangement of chromosomes and exchange of genetic material, with chromosome 9. BCR is a gene found on chromosome 22, but the exchange of information causes a gene fusion with ABL, a gene found on chromosome 9, creating a new gene called BCR-ABL. BCR-ABL encodes for a different protein that is responsible for the growth of abnormal cells. Drug treatments for CML, like imatinib (Gleevec), which was approved by the FDA in 2001 for the treatment of CML and has shown high rates of remission in patients living with CML, work by blocking a certain enzyme called tyrosine kinase which is produced by the BCR-ABL gene.

Dr. Nowell, who is now a professor of pathology and laboratory medicine at University of Pennsylvania's School of Medicine and the first director of the school's Abramson Cancer Center, called the progress in the last 50 years gratifying. "We now have a treatment that specifically attacks the abnormal production of proteins caused by the genetic mutation," he said, referring to therapies such as Gleevec. There are an estimated 24,800 Americans living with CML, which accounts for 7 to 20 percent of all leukemia cases.

Dr. Nowell stressed the need for pharmaceutical companies to develop new, additional specific therapies for different types of cancer and called the lack of support for basic research on the many different kinds of tumors that can arise from mutations an "obstacle" in cancer research.

When asked whether he thought the Philadelphia chromosome discovery was simply an accident or fate, Dr. Nowell quickly responded with a laugh. "Serendipity, all of the above. I still don't know what questions I had about those cells or what I expected to find, but it was one of the two most important observations of my career."



Natalie Castro is an aspiring physician interested in family and community medicine. She hopes to create awareness of health issues through medical journalism.


Published: December 9, 2010


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