Interferon gamma promotes survival of lymphoblasts overexpressing 9-O-acetylated sialoglycoconjugates in childhood acute lymphoblastic leukaemia (ALL)

Abstract

An enhanced linkage-specific 9-O-acetylated sialic acid (9-O-AcSA) on peripheral blood mononuclear cells (PBMC) of children with acute lymphoblastic leukaemia, ALL (PBMC_ALL, 9-O-AcSA⁺ cells) was demonstrated by using a lectin, Achatinin-H, whose lectinogenic epitope was 9-O-AcSAα2-6GlNAc. Our aim was to evaluate the in vitro contributory role of this glycotope (9-O-AcSAα2-6GalNAc) towards the survival of these 9-O-AcSA⁺ cells in ALL patients. For direct comparison, 9-O-AcSA^- cells were generated by removing O-acetyl group of 9-O-AcSA present on PBMC_ALL using O-acetyl esterase. An elevated level of serum interferon gamma (IFN-γ) in affected children led us to think that PBMC_ALL are continuously exposed specifically to this cytokine. Accordingly, 9-O-AcSA⁺ and 9-O-AcSA^- cells were exposed in vitro to IFN-γ. A twofold increased NO release along with inducible NO synthase (iNOS) mRNA expression by the 9-O-AcSA⁺ cells was observed as compared to the 9-O-AcSA^-cells. The decreased viability of IFN-γ exposed 9-O-AcSA^- cells as compared to 9-O-AcSA⁺ cells were reflected from a 5.0-fold increased caspase-3-like activity and a 10.0-fold increased apoptosis in the 9-O-AcSA^- cells when production of NO was lowered by adding competitive inhibitor of iNOS in reaction mixture. Therefore, it may be envisaged that a link exists between induction of this glycotope and their role in regulating viability of PBMC_ALL. Taken together, it is reasonable to hypothesise that O-acetylation of sialic acids on PBMC_ALL may be an additional mechanism that promotes the survival of lymphoblasts by avoiding apoptosis via IFN-γ-induced NO production.