title: O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia.
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.
authors.affiliation: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, The Saban Research Institute, Children's Hospital Los Angeles, CA 90089, USA.
authors.forename: Reshmi
authors.initials: R
authors.lastname: Parameswaran
authors.forename: Min
authors.initials: M
authors.lastname: Lim
authors.forename: Anna
authors.initials: A
authors.lastname: Arutyunyan
authors.forename: Hisham
authors.initials: H
authors.lastname: Abdel-Azim
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.forename: Kam
authors.initials: K
authors.lastname: Lau
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.forename: Robert K
authors.initials: RK
authors.lastname: Yu
authors.forename: Mark
authors.initials: M
authors.lastname: von Itzstein
authors.forename: Nora
authors.initials: N
authors.lastname: Heisterkamp
authors.forename: John
authors.initials: J
authors.lastname: Groffen
mesh_terms: D000107:Acetylation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use / Q000652:urine; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011743:Pyrimidines; D014750:Vincristine; C498826:nilotinib; D019158:N-Acetylneuraminic Acid