O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

Abstract

In the past decade, aberrant O-GlcNAcylation has emerged as a new hallmark of cancer. O-GlcNAcylation is a post-translational modification that results when the amino-sugar β-D-N-acetylglucosamine (GlcNAc) is made in the hexosamine biosynthesis pathway (HBP) and covalently attached to serine and threonine residues in intracellular proteins by the glycosyltransferase O-GlcNAc transferase (OGT). O-GlcNAc moieties reflect the metabolic state of a cell and are removed by O-GlcNAcase (OGA). O-GlcNAcylation affects signaling pathways and protein expression by cross-talk with kinases and proteasomes and changes gene expression by altering protein interactions, localization, and complex formation. The HBP and O-GlcNAcylation are also recognized to mediate survival of cells in harsh conditions. Consequently, O-GlcNAcylation can affect many of the cellular processes that are relevant for cancer and is generally thought to promote tumor growth, disease progression, and immune escape. However, recent studies suggest a more nuanced view with O-GlcNAcylation acting as a tumor promoter or suppressor depending on the stage of disease or the genetic abnormalities, proliferative status, and state of the p53 axis in the cancer cell. Clinically relevant HBP and OGA inhibitors are already available and OGT inhibitors are in development to modulate O-GlcNAcylation as a potentially novel cancer treatment. Here recent studies that implicate O-GlcNAcylation in oncogenic properties of blood cancers are reviewed, focusing on chronic lymphocytic leukemia and effects on signal transduction and stress resistance in the cancer microenvironment. Therapeutic strategies for targeting the HBP and O-GlcNAcylation are also discussed.

Single cell and bulk RNA expression analyses identify enhanced hexosamine biosynthetic pathway and O-GlcNAcylation in acute myeloid leukemia blasts and stem cells

“…Bulk AML cells show enhanced HBP activity and O-GlcNAcylation compared t0 PBMCs and chemotherapeutic drugs have been shown to further enhance O-GlcNAcylation in AML cells ( 19 , 22 , 23 ). In this manuscript, we use bulk cells to refer to MNC from blood or bone marrow in AML patients and AML blasts to refer to non-LSC AML cells.…”

“…Increased O-GlcNAcylation is implicated in both hematopoietic and solid cancers where it controls cell proliferation and metastasis ( 17 , 18 ). O-GlcNAcylation is a key player in hematological malignancies such as chronic lymphocytic leukemia (CLL), pre-B-cell acute lymphocytic leukemia (preB ALL) and AML ( 19 ). Specific O-GlcNAcylation of signal transducer and activator of transcription 5 (STAT5) at threonine 92 has been reported both in CLL and AML cells.…”

Protein O‐GlcNAcylation: The sweet hub in liver metabolic flexibility from a (patho)physiological perspective

“…Several studies have reported that hyper O-GlcNAcylation seems to be a common feature in a variety of cancers, including liver cancer, 35,177 breast cancer, 13 uterine cancer, 178 prostatic cancer, 179 colorectal cancer 180 and pancreatic cancer, 94,181 and even non-solid cancers such as acute myeloid leukaemia and other blood cancers. 26,182 Hyper O-GlcNAcylation in cancer cells is mainly attributed to disruption of O-GlcNAcylation cycle homeostasis and abnormal expression of its process enzymes. 183 The proteins and involved are described in Figure 8.…”

O-GlcNAcylation: an important post-translational modification and a potential therapeutic target for cancer therapy

“…In addition to solid tumors, there are many reports about the role of O -GlcNAcylation in various blood cancers (Spaner 2021 ). Shi et al (Shi et al 2010 ) reported increased O -GlcNAcylation and OGT in chronic lymphocytic leukemia (CLL) cells compared with those in normal lymphocytes, and also revealed that this is caused by higher levels of the sugar donor UDP-GlcNAc.…”