Critical weakness in leukemic cells may be breakthrough for new treatments

New research indicates that leukemic cells can be eradicated by removing a carbohydrate modification that is displayed on the cell's surface. This discovery is an important advance against leukemia.

Leukemia is a cancer of malignant white blood cells that multiply uncontrollably. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer.

"We have found that the leukemic cell has an altered cell surface carbohydrate decoration compared to normal cells and this also conveys resistance to drug treatment," said Professor Mark von Itzstein, Director of Griffith University's Institute for Glycomics at the Gold Coast Campus in Queensland, Australia. "We have now shown that with the removal of this carbohydrate alteration the cells die."

This research, a collaboration between von Itzstein and Nora Heisterkamp and John Groffen, both of The Saban Research Institute of Children's Hospital Los Angeles, was published the Journal of Experimental Medicine (2013; doi:10.1084/jem.20121482).

von Itzstein said the research could lead to new ways to fight the disease, particularly where it has become treatment resistant. The investigators found that 9-O-acetylated N-acetylneuraminic acid (Neu5Ac) was strongly induced in ALL cells with resistance to vincristine or nilotinib, which are drugs with distinct cytotoxic mechanisms. Removing Neu5Ac from the cell surface made the ALL cells more vulnerable to such drugs. Neu5Ac was demonstrated to be essential to the survival of ALL cells, and removing O-acetylation may be useful as therapy to eradicate drug-resistant ALL cells.

"Up until 40 years ago, only one child in five survived ALL, but advances in chemotherapy have changed that outcome and now nearly 80% of children with ALL will be cured. For the remaining 20%, however, the disease returns necessitating additional rounds of intensive chemotherapy. Unfortunately, most relapsed patients die within one year because their cancer cells are resistant to chemotherapy. In the future, we hope that this novel, structural approach to treating ALL may offer an effective treatment option for children battling drug-resistant forms of the disease," said von Itzstein.

Von Itzstein said the discovery had been made possible only through a unique sharing of research expertise.

"These results are the culmination of an international collaboration that commenced only a few years ago when Professor Groffen spent study leave in the Institute for Glycomics on Griffith's Gold Coast Campus. It has been a wonderful opportunity to combine the US team's internationally acclaimed expertise in leukemia with our own expertise in carbohydrate science. By exploiting this Achilles' heel in these leukemic cells, our collaborative research efforts are now focused on the development of a new type of drug therapy that targets this carbohydrate modification," said von Itzstein.

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