Unstable leukemia stem cells may predispose patients to drug resistance

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The BCR-ABL gene in chronic myeloid leukemia stem cells has a tendency to quickly mutate, and this may help explain why patients are predisposed to resistance to drugs like imatinib that target that gene, according to a study in the May 2 Journal of the National Cancer Institute.

Treatment with imatinib causes clinical remissions in most patients with chronic myeloid leukemia, but relapses are common and the cancer can become resistant to the drug. The oncogene, BCR-ABL, is the cause of chronic myeloid leukemia. Researchers have hypothesized that the relapses are due to chronic myeloid leukemia stem cells with specific BCR-ABL gene mutations that make them resistant to the drug long before they are exposed to it.

Xiaoyan Jiang, M.D, Ph.D., and Connie Eaves, Ph.D., of the British Columbia Cancer Agency in Vancouver, and colleagues isolated chronic myeloid leukemia stem cells from patients and analyzed them to identify mutations in the BCR-ABL gene.

The stem cells were found to be genetically unstable and had a high frequency of mutations, even in the absence of imatinib. The researchers identified more than 70 BCR-ABL mutations in the stem cells and their immediate progeny, many of which would be expected to alter the BCR-ABL protein, the target of imatinib. This could result in resistance to the drug.

"Although this study was not designed to identify mutations that would contribute to disease progression, our results suggest that these would also be found. These considerations highlight the importance of gaining further understanding of the control of DNA replication and repair in the leukemic stem cells from patients with chronic phase [chronic myeloid leukemia] in future efforts to devise therapies with curative potential," the authors write.

In an accompanying editorial, Margret Rodrigues, Ph.D., and Martin Sattler, Ph.D., of the Dana Farber Cancer Institute in Boston, discuss the possible causes of genetic instability in the BCR-ABL gene and future approaches to developing successful therapies for chronic myeloid leukemia. "A future challenge will be to devise approaches that overcome drug resistance within these [chronic myeloid leukemia stem] cells without selecting for additional drug-resistant populations," the authors write.

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