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The Faulty Gene Behind Chronic Myeloid Leukemia

Posted Aug 24 2008 1:49pm
ANNOUNCER: Scientists today know a great deal about chronic myeloid leukemia. The story of their research into the disease goes back 40 years, to a lab in Philadelphia. Peter Nowell at the University of Pennsylvania stumbled on a technique to make the chromosomes of dividing cells visible under the microscope. Nowell showed slides of chromosomes from CML patients to a young graduate student, David Hungerford. Hungerford spotted what appeared to be an abnormally small chromosome in each of the samples.

PETER NOWELL, MD: He spotted a very small chromosome in one type of human leukemia. It was there in essentially every cell, and it was there in essentially every case. So this argued very strongly that this altered abnormal chromosome was playing a role in the development of this tumor.

ANNOUNCER: Nowell and Hungerford's discovery would soon be called the "Philadelphia Chromosome." For them, it suggested a genetic cause for leukemia. But others weren't so sure. It could also be the other way around, that leukemia caused chromosomal damage.

PETER NOWELL, MD: Some people didn't want to believe that a genetic alteration was involved in the development of cancer. And when I talk about "genetic" here, I'm talking about somatic genetics. This is a change in one cell that allows the progeny of that cell to grow out as a tumor.

JOHN M. GOLDMAN, MD: There was quite a period during which there was a legitimate debate as to whether this Philadelphia chromosome was just a marker, was just an index of something gone wrong or whether it was actually the cause of the real pathogenesis of this disease.

ANNOUNCER: Nowell and Hungerford had discovered that patients with chronic myeloid leukemia-or CML-often had a chromosome that was missing a piece. It took more than a decade before anyone found what happened to it.

JOHN GOLDMAN, MD: Not much happened until 1973 when Janet Rowley, a very eminent cytogeneticist working in Chicago, discovered that in fact, it was not loss of chromosomal material from chromosome 22, it was exchange of chromosomal material between 9 and 22. So 22 became shorter and 9 became longer.

JANET ROWLEY, MD: There were new technical advances that occurred in 1970, leading to chromosome banding where there is a unique pattern of dark and light staining areas on chromosomes.

ANNOUNCER: Janet Rowley and other scientists now could distinguish clearly among the 23 chromosomes pairs in the human cell. And by analyzing photographs of leukemia cells taken under a microscope, Rowley solved the puzzle. She found out what had happened to the missing piece of the Philadelphia chromosome. Two chromosomes switched parts, what's called a "translocation." Rowley made her discovery at home, where she often worked while raising children.

JANET ROWLEY, MD: I worked on the dining room table because it was the biggest, clear surface in the house where you could spread out 15 or 20 photographs and look first at one and then another and then see that the same abnormality was present. It was a moment of great elation because I was not looking for translocations; they didn't exist.

ANNOUNCER: Ten years later, researchers started understanding the genetic damage caused by the translocation. They learned it created a new gene called BCR-Able.

JOHN GOLDMAN, MD: So you now have on the Philadelphia chromosome a fusion gene composed of parts of two normal genes, which never normally come together.

ANNOUNCER: The new gene creates an enzyme that interferes with signals that regulate white blood cells, causing an explosion in their growth, the hallmark of chronic myeloid leukemia.

JANET ROWLEY, MD: Normally, these signals are very intermittent, and well regulated, of course. Now what happens is that these signals are present more constantly and at a higher level, so the cell is receiving false signals to grow and divide in an inappropriate way.

ANNOUNCER: In the mid 1980s, the rouge enzyme was identified as a type called a tyrosine kinase. They were being studied in several labs around the world. One team of scientists sought ways to block their action in CML.

JOHN GOLDMAN, MD: It then became attractive to see whether you could develop basic molecules in the chemical laboratory that would block the action of these kinases. So again, in the early 1990s, a pharmaceutical company in Switzerland, Ciba-Geigy, and many other pharmaceutical companies, started programs of developing small molecules that would inhibit tyrosine kinases. Out of that program came STI-571, signal transduction inhibitor-571, now known as imatinib.

ANNOUNCER: In early tests and later, in clinical trials, imatinib proved very effective against chronic myeloid leukemia. Trials showed imatinib worked well in returning a CML patient's elevated white blood counts to normal, what's called a good hematologic response. What imatinib proved it did better than other drugs was reducing the number of white blood cells shown to contain the Philadelphia chromosome.

JOHN GOLDMAN, MD: The incidence of complete hematological control is probably better with imatinib, but what's really impressive is that the instance of complete chromosomal control, complete elimination of the Philadelphia chromosome in the bone marrow of patients, is now about 70% with imatinib, compared with 10% with interferon-alpha and cytarabine.

ANNOUNCER: Doctors think this good chromosomal control with imatinib, which is now known as Gleevec, may lead to longer survival in many patients. Peter Nowell, David Hungerford, and Janet Rowley, had no way of knowing where their pioneering research would lead. But they contributed tremendously to our understanding of the genetics of at least some types of cancer. And their work led to a drug that is helping many patients with chronic myeloid leukemia.

JANET ROWLEY, MD: I get calls now from patients relating my discovery to their response to Gleevec, the quality of life that they presently have. That's just a marvelous feeling.

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