Leukemic Cells Escape Cancer Drug in Bone Marrow

The cancer drug asparaginase fails to help cure some children with acute lymphoblastic leukemia (ALL) because molecules released by certain cells in the bone marrow counteract the effect of that drug.

Investigators at St. Jude Children's Research Hospital (Memphis, TN, USA) showed that mesenchymal cells in the bone marrow create a protective niche for leukemic cells by releasing large amounts of asparagine, an amino acid that nearby leukemic cells must have to survive but do not make efficiently. This extra supply of asparagine helps leukemic cells survive treatment with asparaginase, a drug that normally would deplete their supply of this vital nutrient.

The study's findings also suggest that drugs now being developed to block the enzyme that makes asparagine should be tested to see if they also prevent mesenchymal cells from making this amino acid. In addition, the ability of mesenchymal cells to make asparagine might be decreased by cancer drugs that are already known to disrupt the activity of those cells.

Leukemic cells that resist asparaginase and survive in this protective niche of the bone marrow might be the reason that leukemia recurs in some children who have been treated with this drug, said Dario Campana, M.D., Ph.D., a member of the oncology and pathology departments at St. Jude. Dr. Campana is senior author of a report that appears in the March 2007 online pre-publication issue of The Journal of Clinical Investigation.

This insight from this study will help researchers to find ways to disrupt this safe haven for leukemic cells that need asparagine, added James R. Downing, M.D., St. Jude scientific director and chair of the pathology department. Dr. Downing is a co-author of paper.

Because asparaginase is so widely used to treat ALL, this new insight into how mesenchymal cells protect leukemic cells is very important, said Ching-Hon Pui, M.D., chair of the oncology department and American Cancer Society professor at St. Jude. The more we learn about the molecular interactions between these cells, the more likely we'll be able to enhance the anti-leukemic action of asparaginase and perhaps other anti-leukemic drugs as well, said Dr. Pui, a co-author of the paper. That would reduce the rate of recurrence of ALL and continue our successful efforts to increase the survival rate of ALL.


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