Bar Harbor, Maine -- The abberant Philadelphia chromosome is not a problem local to Philadelphia, but that's where researchers discovered the genetic mutation that's the root cause of some leukemias, including chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). Led by Shaoguang Li, M.D., Ph.D., researchers at The Jackson Laboratory, in collaboration with scientists at Bristol-Myers Squibb Oncology, are discovering startling new information about the mechanisms of Philadelphia-positive (Ph+) leukemias that will affect how they are treated clinically.
The Philadelphia Chromosome is actually a faulty mixture of two chromosomes, 9 and 22, which typically work perfectly well independent of each other. But in rare circumstances they physically exchange genetic material in a specific way, and the combined Philadelphia chromosome merges two harmless genes into something destructive. The resulting protein, called BCR-ABL, unleashes a cascade of events that ultimately leads to unregulated cell proliferation in blood cells, leading to Ph+ leukemia.
Bone marrow transplants can cure these leukemia patients, but the procedure could be risky, and sufficiently compatible donors often cannot be found. Therefore the drug imatinib mesylate (sold by the pharmaceutical company Novartis as Gleevec), which disables the destructive function of the BCR-ABL protein, represented a huge step forward in treatment, especially for CML in chronic phase. Imatinib doesn't cure CML, but it inhibits the deadly cascade launched by BCR-ABL, and most patients can use it to better manage the disease with minimal side effects.
While imatinib helps many human patients, Li is using mice with the equivalent of the Ph+ leukemias to investigate why some do not respond to it. Also, imatinib has little positive effect for Ph+ leukemia patients that have progressed to blast crisis, the phase during which the cancer cells undergo additional changes that
Contact: Mark Wanner