American Association for Cancer Research
15357163mct180426-sup-200658_2_supp_4886795_pbpr3d.pdf (1.62 MB)

Figure S4 from Hexosamine Biosynthetic Pathway Inhibition Leads to AML Cell Differentiation and Cell Death

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journal contribution
posted on 2023-04-03, 16:02 authored by Abhishek Asthana, Parameswaran Ramakrishnan, Yorleny Vicioso, Keman Zhang, Reshmi Parameswaran

siRNA mediated OGT silencing reduces proliferation and induce apoptosis.


Athymic Animal and Hemapoietic Biorepository and Cellular therapy core facilities, Shared Resources of the Case Comprehensive Cancer Center


St.Baldrick's Foundation

Mizutani foundation for Glycoscience

B positive foundation

Children's Leukemia association



Treatment for acute myeloid leukemia (AML) has remained unchanged for past 40 years. Targeting cell metabolism is a promising avenue for future cancer therapy. We found that enzymes involved in metabolic hexosamine biosynthetic pathway (HBP) are increased in patients with AML. Inhibiting GFAT (the rate-limiting enzyme of HBP) induced differentiation and apoptosis in AML cells, sparing normal cells. UDP-GlcNAc, the end product of HBP, is the substrate for O-GlcNAcylation, a posttranslational modification. O-GlcNAc transferase (OGT) is the enzyme which transfers GlcNAc from UDP-GlcNAc to target proteins. Inhibition of O-GlcNAcylation, using OGT inhibitors as well as genetic knockdown of OGT, also led to cell differentiation and apoptosis of AML cells. Finally, HBP inhibition in vivo reduced the tumor growth in a subcutaneous AML xenograft model and tumor cells showed signs of differentiation in vivo. A circulating AML xenograft model also showed clearance of tumor load in bone marrow, spleen, and blood, after HBP inhibition, with no signs of general toxicity. This study reveals an important role of HBP/O-GlcNAcylation in keeping AML cells in an undifferentiated state and sheds light into a new area of potential AML therapy by HBP/O-GlcNAc inhibition. Mol Cancer Ther; 17(10); 2226–37. ©2018 AACR.

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