Philadephia – the birthplace of cancer genetics

The 28th September 2010 was declared “Philadelphia Chromosome Day“. The city of Philadelphia celebrated 50 years since a landmark discovery in cancer research. A special symposium to celebrate the Philadelphia Chromosome heard testimonies from chronic myeloid leukaemia survivors – including basketball legend Kareem Abdul-Jabbar – who were grateful to be alive thanks the discovery of this tiny chromosome and the research that followed. The Philadelphia chromosome story is a good example of how curiosity, careful observation, persistence and some luck can lead to breakthrough cancer treatment.

DNA is a long molecule that carries our genes, which are the instructions for how our bodies are made and work. It’s usually unravelled as a shapeless structure (blob would be a good word) called the nucleus, where it sends off messages to the cell, and makes a copy of itself. When the cell’s ready to divide into two daughter cells, the DNA takes shape to become recognisable chromosomes. We can see these with a microscope.

We can see large changes to the chromosomes down the microscope. These changes can be very helpful because they tell us that the DNA has been reorganised. Very specific changes can help us find important genes.

Visible chromosome changes are often bad news. In an embryo they usually mean death or disability. Down Syndrome is the best known example, where a person has an extra copy of every gene on the smallest chromosome, chromosome 21. Whole extra copies of other chromosomes are overwhelmingly fatal to the embryo. When chromosomes change somewhere in the body this can cause cancer.

There’s one abnormal chromosome we still refer to by the town where it was discovered – the Philadelphia Chromosome. It has a remarkable history. It was the first cancer chromosome to be discovered and the first cancer gene abnormality to get a designer drug.

In 1956 Peter Nowell started studying the chromosomes in the cells of leukaemia patients at the University of Pennsylvania in Philadelphia. In chronic myeloid leukaemia (CML) cells his collaborator David Hungerford found a very small abnormal chromosome that was in the leukaemia cells but not in the blood (non-cancerous) cells. So it looked like the change was associated with the leukaemia –- perhaps it caused the leukaemia.

The only other likely cancer chromosome abnormality discovered around the same time was the “Christchurch Chromosome” in chronic lymphocytic leukaemia (CLL). But according to Peter Nowell the Christchurch Chromosome turned out to be an inherited non-cancer chromosome anomaly*. In those days the Committee for the Standardization of Chromosomes recommended naming an abnormal chromosome after the city where it was discovered. This practice has been dropped, and now abnormal chromosomes are named by the chromosomes involved  and a shorthand description of what’s changed.

Nowell and Hungerford’s chromosome, which was called the “Philadelphia Chromosome”, was thought to be a cut-off chromosome 21. All they had to tell chromosomes apart by was their shape. Chromosomes 21 and 22 looked much the same. Chromosome 9 was one of eight pairs of chromosomes of similar size and shape, so they didn’t realise that a chromosome 9 was also abnormal.

In the 1970s techniques were developed for banding chromosomes so that they could all be told apart. By looking at banded chromosomes Janet Rowley showed that the missing part of what was actually chromosome 22 had moved to the bottom of chromosome 9.

We now know that the two chromosomes actually swap their ends – the end of chromosome 9 goes onto 22 and vice versa. This is called a translocation. Many translocations in cancer are very precise – so time and again the same distinctive chromosome swaps are found in the same type of cancer, and they join the same two genes together each time.

 

These banded chromosomes show how the ends of chromosomes 9 and 22 are swapped to make the Philadelphia chromosome that causes chronic myeloid leukaemia.
These banded chromosomes show how the ends of chromosomes 9 and 22 are swapped to make the Philadelphia chromosome that causes chronic myeloid leukaemia.

 

The 1980s saw an explosion of cancer gene discoveries. They made use of the fact that the chromosomes broke and rejoined within the cancer genes. So when you found where the DNA broke, you had found your cancer gene.

The Philadelphia translocation joins the end part of the ABL1 cancer gene (oncogene) to the front part of the BCR gene. ABL stands for Abelson – this gene was discovered in the Abelson mouse virus. And in one of the historical quirks of gene naming BCR stands for breakpoint cluster region. ABL1 is a gene controlling aspects of cell growth and division. It’s a proto-oncogene, which means it’s a gene that can be made to become an oncogene by making it work faster or harder. We’re not sure what BCR does, but the front end of a gene controls how fast it works. Putting the ABL1 gene under the control of the BCR switch turns it into a cancer gene. This is one of the most specific chromosome abnormalities that we know of in cancer. Most people with chronic myeloid leukaemia have a Philadelphia chromosome in their leukaemia cells.

The last part of the story is the “miracle cure”. Brian Drucker was convinced that by knowing the shape of the Bcr-Abl protein (a “kinase”) made by the BCR-ABL1 gene one could design a chemical that fits into the active site and block it. He teamed up with Ciba-Geigy (now Novartis), who made a promising kinase inhibitor, and set up clinical trials. The rest is history. There was a 100% remission rate early in the phase I clinical trial and the drug imatinib mesylate (also known as Gleevec or Glivec,) was fast-tracked for patient treatment. CML used to be a certain death sentence. There’s now a very good remission rate.

This is a neat example of how knowing the biology of a cancer can be used to develop drugs that are very specific and effective. Unfortunately most cancers have more complicated genetics, but the more we understand them the more chance we have of being able to develop treatments like imatinib, that attack the cancer cells and leave healthy cells alone.

With its special place in the history of cancer cytogenetics we still know it as the Philadelphia Chromosome (or Philly for short). It’s even official.

FURTHER READING

Chandra, H. et al. 2011. Philadelphia Chromosome Symposium: commemoration of the 50th anniversary of the discovery of the Ph chromosome. Cancer Genetics 204:171-9.

Druker, B. J. et al. 1996. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Medicine 2, 561–566.

Druker, B. J. et al. 2001. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New England Journal of Medicine 344, 1031–1037.

Nowell, P.C. and Hungerford, D.A. 1961. Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J. Natl. Cancer Inst. 27:1013-1035.

de Klein, A. et al. 1982. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300(5894):765-7.

Groffen, G. et al. 1984. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36(1):93-9.

* According to Peter Nowell, as cited in the link, the Christchurch chromosome was not a cancer chromosome. This information is difficult to find but makes sense in light of what we now know about cancer chromosomes. Modern medical dictionaries describe it as a chromosome in leukaemia patients in line with the original publication.