Epigenetic activation of O-linked β-N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia

Kampa-Schittenhelm, Kerstin M; Haverkamp, Thomas; Bonin, Malte von; Tsintari, Vasileia; Bühring, Hans‐Jörg; Haeusser, Lara; Blumenstock, Gunnar; Dreher, Simone; Ganief, Tariq; Akmut, Figen; Illing, Barbara; Mau-Holzmann, Ulrike A.; Bonzheim, Irina; Schleicher, Emily M.; Vogel, Wichard; Schittenhelm, Marcus M

doi:10.1016/j.ebiom.2020.102678

Cited by 12 publications

(11 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pretreatment with PUGNAC also prevented engraftment of leukemic cell-lines expressing a mutant form of ASXL1 in immunodeficient mice but not leukemic cells expressing another oncogene (177). Consistent with these findings, differentiation of leukemic blasts by cannabinoids produced clinical responses associated with increased expression of OGT in vitro and in vivo (178). Cannabinoidmediated differentiation of Jurkat and MOLMM14 cell-lines used to model acute leukemia in vitro was blocked by genesilencing of OGT and enhanced by increasing O-GlcNAcylation with the OGA inhibitor TMG (178).…”

Section: Amlsupporting

confidence: 62%

“…Consistent with these findings, differentiation of leukemic blasts by cannabinoids produced clinical responses associated with increased expression of OGT in vitro and in vivo ( 178 ). Cannabinoid-mediated differentiation of Jurkat and MOLMM14 cell-lines used to model acute leukemia in vitro was blocked by gene-silencing of OGT and enhanced by increasing O-GlcNAcylation with the OGA inhibitor TMG ( 178 ).…”

Section: O-glcnacylation In Other Hematological Malignanciesmentioning

confidence: 62%

See 1 more Smart Citation

O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

Spaner

2021

Front. Immunol.

View full text Add to dashboard Cite

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.

show abstract

Section: Amlsupporting

confidence: 62%

Section: O-glcnacylation In Other Hematological Malignanciesmentioning

confidence: 62%

O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

Spaner

2021

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…7 ). Homeostasis of O - GlcNAc through activities of OGT and OGA has been previously implicated in normal hematopoietic development 96 , 97 , in differentiation arrest of AML and Jurkat T‑cells 98 as well as in other cancers 99 . However, our study is the first to report that this modification is also essential for the survival of MLL-r B-ALL cells.…”

Section: Discussionmentioning

confidence: 99%

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Oliveira¹,

Zhang²,

Joo³

et al. 2021

Theranostics

View full text Add to dashboard Cite

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi- omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi- omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi- omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.

show abstract

“…Inhibition of the differentiation blockage in acute myeloid leukemia has been shown to be the most successful target in leukemia therapy. Dronabinol, the enantiomer (−)- trans -Δ 9 -tetrahydrocannabinol approved by the FDA for conditions like HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting, was found to inhibit the differentiation blockage in acute leukemia cells in vitro and that O-linked-β- N -acetyl glucosamine transferase was fundamental to this process [ 65 ].…”

Section: Cannabinoidsmentioning

confidence: 99%

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Tomko

Whynot

Ellis

et al. 2020

Cancers

149

139

View full text Add to dashboard Cite

In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.

show abstract

Epigenetic activation of O-linked β-N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia

Cited by 12 publications

References 55 publications

O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

Contact Info

Product

Resources

About