Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase
Shotaro Iwamoto, … , Ching-Hon Pui, Dario Campana
Shotaro Iwamoto, … , Ching-Hon Pui, Dario Campana
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):1049-1057. https://doi.org/10.1172/JCI30235.
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Research Article Oncology

Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase

Abstract

Because of their low asparagine synthetase (ASNS) expression and asparagine biosynthesis, acute lymphoblastic leukemia (ALL) cells are exquisitely sensitive to asparagine depletion. Consequently, asparaginase is a major component of ALL therapy, but the mechanisms regulating the susceptibility of leukemic cells to this agent are unclear. In 288 children with ALL, cellular ASNS expression was more likely to be high in T-lineage ALL and low in B-lineage ALL with TEL-AML1 or hyperdiploidy. However, ASNS expression levels in bone marrow–derived mesenchymal cells (MSCs), which form the microenvironment where leukemic cells grow, were on average 20 times higher than those in ALL cells. MSCs protected ALL cells from asparaginase cytotoxicity in coculture experiments. This protective effect correlated with levels of ASNS expression: downregulation by RNA interference decreased the capacity of MSCs to protect ALL cells from asparaginase, whereas enforced ASNS expression conferred enhanced protection. Asparagine secretion by MSCs was directly related to their ASNS expression levels, suggesting a mechanism — increased concentrations of asparagine in the leukemic cell microenvironment — for the protective effects we observed. These results provide what we believe to be a new basis for understanding asparaginase resistance in ALL and indicate that MSC niches in the bone marrow can form a safe haven for leukemic cells.

Authors

Shotaro Iwamoto, Keichiro Mihara, James R. Downing, Ching-Hon Pui, Dario Campana

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Figure 2

MSCs protect ALL cells from asparaginase cytotoxicity.

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MSCs protect ALL cells from asparaginase cytotoxicity. The ALL cell line...
The ALL cell lines 380, REH, and RS4;11 were cultured with and without MSCs for 48 hours in the presence of the concentration of asparaginase that causes 50% killing in 2 days of culture, as previously determined for each cell line in experiments without MSCs (1.0 IU/ml for 380 and REH; 0.001 IU/ml for RS4;11). Values are mean ± SD of cell killing obtained in cultures with MSCs relative to that obtained in parallel cultures without MSCs. Ten experiments were performed for each ALL cell line with TERT-immortalized MSCs; MSCs from 9 healthy donors and 13 patients with ALL in complete remission were also tested for each ALL cell line. Each experiment consisted of 4 measurements.