by Darrin S. Joy and Alicia Di Rado



City of Hope’s WenYong Chen, Ph.D., is studying a gene that might extend lifespan — or maybe limit it. The same gene sometimes fights cancer — but it can promote the disease, too.

WenYong Chen searches for ways to block chronic myelogenous leukemia. (Photo by Darrin S. Joy)

These are the scientific mysteries of sirtuin 1, or SIRT1, the so-called “longevity gene.” Pharmaceutical companies are investigating the gene for its role in diseases of aging such as Alzheimer’s. But Chen is interested in an entirely different question: how SIRT1 gives the cancerous cells found in chronic myelogenous leukemia, or CML, a survival advantage.

Reporting in the Feb. 23 issue of the journal Blood, Chen, an assistant professor in the Division of Biology, along with Ravi Bhatia, M.D., director of the Division of Hematopoietic Stem Cell and Leukemia Research, and their colleagues recently found growing evidence that SIRT1 may lie behind CML cells’ resistance to the drug known as Gleevec or imatinib. The findings suggest a way to target leukemia more powerfully.

When it was introduced last decade, Gleevec revolutionized treatment of CML, once a fatal disease. Now nine of every 10 leukemia patients taking the drug survive for at least five years, but patients can relapse.

Gleevec fights CML by blocking the mutant protein that kicks off the blood cancer. This protein, BCR-ABL, is the main force that pushes blood stem cells to develop into malignant CML cells and drives them to multiply.

By inactivating BCR-ABL, Gleevec removes that driving force, and leukemia cells wither and die — but not all of them. Some survive and even flourish, and scientists want to know why.

The City of Hope scientists recently showed that leukemia cells produce a lot of SIRT1, and SIRT1 shuts off a gene that suppresses leukemia. That helps leukemia stem cells survive through treatment.

In their latest work, the researchers exposed cells to Gleevec and found that the drug reduced SIRT1 but failed to fully block it.

When the scientists completely blocked SIRT1 using another drug and then added Gleevec, the leukemia cells died — implying that SIRT1 helps the cancerous cells survive.

The team then studied mice with CML. When they inactivated the SIRT1 gene in mice and gave them Gleevec, these mice lived longer than those on Gleevec but with active SIRT1 genes.

Team members believe their work is the first to show that SIRT1 offers a way for leukemia stem cells to survive and develop even when Gleevec successfully blocks BCR-ABL.

“SIRT1 may be an effective therapeutic target for overcoming drug-resistant CML,” Chen said, “but we’ll need further research to confirm that.”

Other authors on the Blood and Carcinogenesis studies (see accompanying story) include Hongfeng Yuan, Ph.D., Zhiqiang Wang, Ph.D., David Horne, Ph.D., Hardik Modi, Mendel Roth, Ph.D., and Hao Zhang, Ph.D. The STOP CANCER Foundation, V Foundation, National Institutes of Health and U.S. Department of Defense funded the work.

Team identifies a new target for leukemia Chronic myelogenous leukemia, or CML, cells can become more abnormal over time. They can gain mutations in the cancer-causing gene BCR-ABL, changing BCR-ABL so that the drug Gleevec no longer recognizes it. By exploring the source of these mutations, WenYong Chen, Ph.D., assistant professor in the Division of Biology and his team may have found another path to fighting CML. They reported those findings in the February issue of Carcinogenesis. The study centered on a protein called Aurora A kinase. Normally, this protein helps cells divide, but it also is highly overactive in many types of cancer, includ-ing CML. The scientists noticed Aurora A levels went down when they gave CML cells Gleevec. Since Gleevec works by blocking BCR-ABL, researchers believe Aurora A is somehow related to BCR-ABL. When the team blocked Aurora A, the CML cells given Gleevec killed themselves. Chen believes Aurora A could be another important new drug target for CML patients, and in particular, for those in advanced phases of the disease. “Inhibiting Aurora A activity may help prevent CML drug resistance and improve disease treatment,” he said.