TKI-resistant human leukemia stem cells are the source of genomic instability

Published on December 12, 2012 at 12:20 PM · No Comments

"We looked at oxidative DNA damage in stem cells, quiescent stem cells and subpopulations of stem cells and found there is elevated oxidative DNA damage in not only the stem cell pool in CML-like mice but also within a sub-population of leukemia stem cells such as long- and short-term stem cells, and quiescent stem cells," said Ms. Bolton Gillespie.

The researchers subsequently examined the genomic instability within leukemic bone marrow cells, and looked for five common point mutations - alterations in single amino acids - that conferred resistance to imatinib. They also examined the cells for other types of alterations and major changes in genes, such as the loss of copies of genes. They found three of the most common point mutations in mouse cells that conferred drug resistance in animals treated with imatinib as well as in those animals that did not receive the drug.

Link to Leukemia in Patients

"We found numerous genetic aberrations that have already been associated with advanced disease in humans," Ms. Bolton Gillespie said. "We were able to mimic the same kind of oxidative DNA damage and genomic instability in this mouse model that is seen in patients."

"It was very important that we found aberrations in the mice that underwent imatinib therapy," Dr. Skorski said. "The assumption now is that even patients undergoing imatinib treatment will continue to accumulate genetic aberrations. These patients may not be safe. As a result, we feel that patients treated with imatinib may benefit from adding a drug that will stop such genetic aberrations. Ongoing research in our lab is aimed at the development of this approach."

Source: Temple University Health System

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