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

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

研究成果: Article査読

228 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1049-1057
ページ数9
ジャーナルJournal of Clinical Investigation
117
4
DOI
出版ステータスPublished - 02-04-2007
外部発表はい

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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