O-acetylation of sialic acids is required for the survival of lymphoblasts in childhood acute lymphoblastic leukemia (ALL).
Exploiting the selective affinity of Achatinin-H towards 9-O-acetylneuraminic acid(alpha2-6)GalNAc, we have demonstrated the presence of 9-O-acetylated sialoglycoproteins (Neu5,9Ac(2)-GPs) on hematopoietic cells of children suffering from acute lymphoblastic leukemia (ALL), indicative of defective sialylation associated with this disease. The carbohydrate epitope of Neu5,9Ac(2)-GPs(ALL) was confirmed by using several synthetic sialic acid analogues. They are functionally active signaling molecules as demonstrated by their role in mediating lymphoproliferative responses and consequential increased production of IFN-gamma due to specific stimulation of Neu5,9Ac(2)-GPs on PBMC(ALL) with Achatinin-H. Cells devoid of 9-O-acetylations (9-O-AcSA(-)) revealed decreased nitric oxide production as compared to 9-O-AcSA(+) cells on exposure to IFN-gamma. Under this condition, a decrease in viability of 9-O-AcSA(-) cells as compared to 9-O-AcSA(+) cells was also observed which was reflected from increased caspase 3 activity and apoptosis suggesting the protective role of this glycotope. These Neu5,9Ac(2)-GPs are also capable of inducing disease-specific anti-Neu5,9Ac(2)-GPs antibodies in ALL children. Additionally, we have observed that disease-specific anti-Neu5,9Ac(2)-GPs have altered glycosylation profile, and they are incapable of exerting a few Fc-glycosylation-sensitive effector functions. These observations hint toward a disbalanced homeostasis, thereby enabling the cancer cells to escape host defense. Taken together, it may be hypothesized that Neu5,9Ac(2)-GPs and their antibodies play a prominent role in promoting the survival of lymphoblasts in ALL.
Ghosh
Shyamasree
S
Immunobiology Division, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India.
Bandyopadhyay
Suman
S
Mukherjee
Kankana
K
Mallick
Asish
A
Pal
Santanu
S
Mandal
Chhabinath
C
Bhattacharya
Dilip K
DK
Mandal
Chitra
C
D000107:Acetylation / Q000187:drug effects; D017304:Annexin A5 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D006413:Hematopoietic System / Q000166:cytology; D006801:Humans; D037102:Lectins / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D018448:Models, Immunological; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000473:pathology*; D012794:Sialic Acids / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
D017304:Annexin A5; D037102:Lectins; D012794:Sialic Acids; D012795:Sialoglycoproteins; C050704:achatinin(H); D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3