O-GlcNAc transferase as an oncogenic regulator in hematologic malignancies: Mechanisms, disease contexts, and therapeutic perspectives.

Authors

Marissa El Hajje, Juan Luiz Coelho-Silva, João Agostinho Machado-Neto, Gustavo Henrique Goulart Trossini

Published in

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Volume 202. Pages 119822. Aug 03, 2026. Epub Aug 03, 2026.

Abstract

O-GlcNAc transferase (OGT) catalyzes the addition of N-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins, coupling cellular metabolic state to the post-translational regulation of hundreds of substrates. Hematologic malignancies exhibit the highest OGT and O-GlcNAcase (OGA) expression levels among all cancer lineages, making this system a unique oncobiological axis in leukemias, lymphomas, and plasma cell dyscrasias. This review provides a disease-specific and mechanistically integrated account of OGT as an oncogenic regulator across the major hematologic entities. We examine the structural biology of the OGT/OGA cycle, its role in normal hematopoiesis, and its coupling to the hexosamine biosynthetic pathway, features that define the primary on-target safety limitation for therapeutic intervention. Disease-specific evidence is addressed for AML, CLL, DLBCL, MCL, multiple myeloma, and associated myeloid malignancies. Four mechanistic axes are identified: immune evasion via PD-L1 stabilization; crosstalk with the phosphoproteome; proteostatic stabilization of MYC, p53, and STAT5; and epigenetic reprogramming via TET/H3K4me3 and EZH2/H3K27me3 circuits. These axes underpin a unified amplifier model explaining why elevated O-GlcNAcylation associates with indolent disease in p53-intact CLL, drives oncogenesis in ASXL1-intact AML, and exerts tumor-suppressive activity in ASXL1-mutant disease. The therapeutic landscape, encompassing OSMI-series inhibitors, HBP-targeting agents, TPR-directed polypeptides, and combination strategies, is reviewed within this framework. ASXL1 mutation status and p53 pathway integrity are identified as the leading stratification biomarkers for clinical translation. Key open questions, including substrate-selective TPR inhibition, phase separation biology, and O-GlcNAcome profiling, are outlined as field priorities.

PMID:
42546407
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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