O-acetylated n-acetylneuraminic acid as a novel target for therapy in human pre-b acute lymphoblastic leukemia

Reshmi Parameswaran, Min Lim, Anna Arutyunyan, Hisham Abdel-Azim, Christian Hurtz, Kam Lau, Markus Müschen, Robert K. Yu, Mark von Itzstein, Nora Heisterkamp, John Groffen

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)805-819
Number of pages15
JournalJournal of Experimental Medicine
Volume210
Issue number4
DOIs
StatePublished - Jun 25 2013

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acids
Acetylesterase
Esterases
Therapeutics
Acetylation
Drug Resistance
Survival
Pharmaceutical Preparations
Vincristine
N-Acetylneuraminic Acid
Cell Survival
Leukemia
Endothelial Cells
Fibroblasts
Cell Count
Carbohydrates
Recurrence
Drug Therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Parameswaran, R., Lim, M., Arutyunyan, A., Abdel-Azim, H., Hurtz, C., Lau, K., ... Groffen, J. (2013). O-acetylated n-acetylneuraminic acid as a novel target for therapy in human pre-b acute lymphoblastic leukemia. Journal of Experimental Medicine, 210(4), 805-819. https://doi.org/10.1084/jem.20121482

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 journalArticle

Parameswaran, R, Lim, M, Arutyunyan, A, Abdel-Azim, H, Hurtz, C, Lau, K, Müschen, M, Yu, RK, von Itzstein, M, Heisterkamp, N & Groffen, J 2013, 'O-acetylated n-acetylneuraminic acid as a novel target for therapy in human pre-b acute lymphoblastic leukemia', Journal of Experimental Medicine, vol. 210, no. 4, pp. 805-819. https://doi.org/10.1084/jem.20121482
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. / O-acetylated n-acetylneuraminic acid as a novel target for therapy in human pre-b acute lymphoblastic leukemia. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 4. pp. 805-819.
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