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, according to St. Jude investigators.
The researchers showed that mesenchymal stem cells (MSCs) 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.
“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, MD, PhD, Oncology and Pathology. Campana is senior author of a report on this work that appears in the April issue of The Journal of Clinical Investigation.
“Insight from this study will help researchers to find ways to disrupt this safe haven for leukemic cells that need asparagine,” said James Downing, MD, scientific director and Pathology chair. Downing is a co-author of the JCI paper.
The study’s findings also suggest that drugs being developed to block the enzyme that makes asparagine should be tested to see if they also prevent MSCs from making this amino acid. In addition, the ability of MSCs to make asparagine might be decreased by cancer drugs already known to disrupt MSC activity.
“Because asparaginase is so widely used to treat ALL, this new insight into how mesenchymal cells protect leukemic cells is very important,” said another co-author, Ching-Hon Pui, MD, Oncology chair.
“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. And that would reduce the rate of recurrence of ALL and continue our successful efforts to increase the survival rate.”
Experiments supporting this study were performed by the paper’s first author, Shotaro Iwamoto, MD, a postdoctoral fellow in Campana’s laboratory, and Keichiro Mihara, a former postdoctoral fellow in that laboratory.