CML: genetic paradigm of targeted therapy 1

Published on September 30, 2015   24 min

A selection of talks on Genetics & Epigenetics

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MICHAEL DEININGER: Hello, I'm Michael Deininger. I'm the chief of the Division of Hematology and Hematologic Malignancies at the University of Utah, Huntsman Cancer Institute. Today, we're going to talk about chronic myeloid leukemia, or CML, genetic paradigm of targeted therapy. The first part of the presentation will focus on the biology of CML, the Philadelphia chromosome, and the development of Imatinib as the first targeted agent tyrosine kinase inhibitor for CML.
The story of chronic myeloid leukemia, or CML, starts in the middle of the 19th century. There were three eminent physicians making major contributions. Alfred Donné, in Paris, was probably the first to recognize leukemia also under the microscope. John Bennet, in Edinburgh, was the first to see a case of CML and describe it. Bennet thought that the case was actually due to an infection, because there was a 'separation of the spleen', as he called it. And just a few weeks later, Rudolf Virchow, in Berlin, described a similar case, but he recognized the neoplastic nature of the disease.
This is a timeline of CML. As I already mentioned, the story goes back to the mid 19th century. The next decades see the realization that leukemia originates from the bone marrow. Then in 1960, Nowell and Hungerford described the Philadelphia chromosome as an abnormally small chromosome 22. This was a seminal discovery, as it the first proof that cancer is the problem, not the DNA, and not the protein. The next few years see the realization that the Philadelphia chromosome is the product of a translocation between chromosomes 9 and 22. And subsequently, the identification of the translocation partners, BCR and ABL1. In 1990, a mouse model was described that reproduced essential disease features. Therapy developed slowly. allogeneic transplant, in 1975, was the first therapy to induce long term remission. But a decade later, interferon alpha was described as the first drug treatment that was effective, at least in a minority of the patients. Then, therapeutic progress accelerates. First, it was recognized that tyrosine kinase activity of BCR-ABL was essential for the disease pathogenesis, and based on that, tyrosine kinase inhibitors were developed. In 1998, phase one trials started testing Imatinib in patients with CML. Then over the subsequent years, we see the rapid evolution of additional therapeutic modalities, that is additional tyrosine kinase inhibitors. And this progress essentially turned CML from a fatal disease into a chronic ailment that can successfully be handled with drugs.