Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase.
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.
Iwamoto
Shotaro
S
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Mihara
Keichiro
K
Downing
James R
JR
Pui
Ching-Hon
CH
Campana
Dario
D
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001215:Asparaginase / Q000627:therapeutic use*; D001216:Asparagine / Q000172:deficiency; D001217:Aspartate-Ammonia Ligase / Q000172:deficiency / Q000235:genetics*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002648:Child; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
D000970:Antineoplastic Agents; D001216:Asparagine; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase