DNA-repair problems destroy hardy leukemia cells

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Leukemia stem cells that overcome drug therapy can be thwarted when deprived of RAD52, a protein key to DNA repair of these cancer cells.

Although the tyrosine kinase inhibitor imatinib effectively targets chronic myeloid leukemia (CML), some patients harbor a small pool of treatment-resistant stem cells that can cause disease progression and relapse, according to a statement issued by Temple University Health System in Philadelphia, Pennsylvania. Tomasz Skorski, MD, PhD, a professor of microbiology and immunology at Temple University School of Medicine, and colleagues reported at the American Society of Hematology annual meeting, held December 8-11, 2012, in Atlanta, Georgia, that they were able to target RAD52 to block the process by which leukemia stem cells repair themselves after anticancer therapy.

“We took advantage of the fact that remaining leukemia stem cells accumulate lots of lethal DNA lesions, but they don't die because they can repair them[selves] very efficiently,” commented Skorski in the Temple statement.

In CML cells, the protein BCR-ABL1, which drives the excessive production of white blood cells, shuts down the main DNA repair system. The leukemia cells then have to rely on a backup pathway for repair. In this backup pathway, DNA repair of CML cells depends on RAD52.

Skorski's team used a peptide molecule known as an aptamer to block RAD52 from binding to DNA. When the aptamer was added to BCR-ABL1-positive bone marrow cells, RAD52 could not bind to the DNA and the leukemic bone marrow cells eventually died. The aptamer had no effect on healthy cells.

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