Abstract
The development of resistance to chemotherapy is a major cause of relapse in acute lymphoblastic leukemia (ALL). Though several mechanisms associated with drug resistance have been studied in detail, the role of carbohydrate modification remains unexplored. Here, we investigated the contribution of 9-O-acetylated N-acetylneuraminic acid (Neu5Ac) to survival and drug resistance development in ALL cells. A strong induction of 9-O-acetylated Neu5Ac including 9-O-acetyl GD3 was detected in ALL cells that developed resistance against vincristine or nilotinib, drugs with distinct cytotoxic mechanisms. Removal of 9-O-acetyl residues from Neu5Ac on the cell surface by an O-acetylesterase made ALL cells more vulnerable to such drugs. Moreover, removal of intracellular and cell surface- resident 9-O-acetyl Neu5Ac by lentiviral transduction of the esterase was lethal to ALL cells in vitro even in the presence of stromal protection. Interestingly, expression of the esterase in normal fibroblasts or endothelial cells had no effect on their survival. Transplanted mice induced for expression of the O-acetylesterase in the ALL cells exhibited a reduction of leukemia to minimal cell numbers and significantly increased survival. This demonstrates that Neu5Ac 9-O-acetylation is essential for survival of these cells and suggests that Neu5Ac de-O-acetylation could be used as therapy to eradicate drug-resistant ALL cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 805-819 |
| Number of pages | 15 |
| Journal | Journal of Experimental Medicine |
| Volume | 210 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jun 25 2013 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
O-acetylated n-acetylneuraminic acid as a novel target for therapy in human pre-b acute lymphoblastic leukemia. / Parameswaran, Reshmi; Lim, Min; Arutyunyan, Anna; Abdel-Azim, Hisham; Hurtz, Christian; Lau, Kam; Müschen, Markus; Yu, Robert K.; von Itzstein, Mark; Heisterkamp, Nora; Groffen, John.
In: Journal of Experimental Medicine, Vol. 210, No. 4, 25.06.2013, p. 805-819.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - O-acetylated n-acetylneuraminic acid as a novel target for therapy in human pre-b acute lymphoblastic leukemia
AU - Parameswaran, Reshmi
AU - Lim, Min
AU - Arutyunyan, Anna
AU - Abdel-Azim, Hisham
AU - Hurtz, Christian
AU - Lau, Kam
AU - Müschen, Markus
AU - Yu, Robert K.
AU - von Itzstein, Mark
AU - Heisterkamp, Nora
AU - Groffen, John
PY - 2013/6/25
Y1 - 2013/6/25
N2 - The development of resistance to chemotherapy is a major cause of relapse in acute lymphoblastic leukemia (ALL). Though several mechanisms associated with drug resistance have been studied in detail, the role of carbohydrate modification remains unexplored. Here, we investigated the contribution of 9-O-acetylated N-acetylneuraminic acid (Neu5Ac) to survival and drug resistance development in ALL cells. A strong induction of 9-O-acetylated Neu5Ac including 9-O-acetyl GD3 was detected in ALL cells that developed resistance against vincristine or nilotinib, drugs with distinct cytotoxic mechanisms. Removal of 9-O-acetyl residues from Neu5Ac on the cell surface by an O-acetylesterase made ALL cells more vulnerable to such drugs. Moreover, removal of intracellular and cell surface- resident 9-O-acetyl Neu5Ac by lentiviral transduction of the esterase was lethal to ALL cells in vitro even in the presence of stromal protection. Interestingly, expression of the esterase in normal fibroblasts or endothelial cells had no effect on their survival. Transplanted mice induced for expression of the O-acetylesterase in the ALL cells exhibited a reduction of leukemia to minimal cell numbers and significantly increased survival. This demonstrates that Neu5Ac 9-O-acetylation is essential for survival of these cells and suggests that Neu5Ac de-O-acetylation could be used as therapy to eradicate drug-resistant ALL cells.
AB - The development of resistance to chemotherapy is a major cause of relapse in acute lymphoblastic leukemia (ALL). Though several mechanisms associated with drug resistance have been studied in detail, the role of carbohydrate modification remains unexplored. Here, we investigated the contribution of 9-O-acetylated N-acetylneuraminic acid (Neu5Ac) to survival and drug resistance development in ALL cells. A strong induction of 9-O-acetylated Neu5Ac including 9-O-acetyl GD3 was detected in ALL cells that developed resistance against vincristine or nilotinib, drugs with distinct cytotoxic mechanisms. Removal of 9-O-acetyl residues from Neu5Ac on the cell surface by an O-acetylesterase made ALL cells more vulnerable to such drugs. Moreover, removal of intracellular and cell surface- resident 9-O-acetyl Neu5Ac by lentiviral transduction of the esterase was lethal to ALL cells in vitro even in the presence of stromal protection. Interestingly, expression of the esterase in normal fibroblasts or endothelial cells had no effect on their survival. Transplanted mice induced for expression of the O-acetylesterase in the ALL cells exhibited a reduction of leukemia to minimal cell numbers and significantly increased survival. This demonstrates that Neu5Ac 9-O-acetylation is essential for survival of these cells and suggests that Neu5Ac de-O-acetylation could be used as therapy to eradicate drug-resistant ALL cells.
UR - http://www.scopus.com/inward/record.url?scp=84878657646&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878657646&partnerID=8YFLogxK
U2 - 10.1084/jem.20121482
DO - 10.1084/jem.20121482
M3 - Article
C2 - 23478187
AN - SCOPUS:84878657646
VL - 210
SP - 805
EP - 819
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -