scholarly journals O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
David E. Spaner
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Protein Interactions ◽  
Immune Escape ◽  
Amino Sugar ◽  
Lymphocytic Leukemia ◽  
Tumor Promoter ◽  
Post Translational Modification ◽  
Promote Tumor Growth ◽  
Hexosamine Biosynthesis ◽  
Glcnac Transferase

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.

scholarly journals Mirs-138 and -424 Control Palmitoylation-Dependent CD95-Mediated Cell Death By Targeting Acyl Protein Thioesterases 1 and 2 in Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1953-1953
Author(s):  
Valeska Berg ◽  
Marion Rusch ◽  
Nachiket Vartak ◽  
Christian Juengst ◽  
Astrid Schauss ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Protein Transport ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Mrna Level ◽  
Resonance Energy ◽  
Lymphocytic Leukemia ◽  
Luciferase Reporter ◽  
Fluorescence Lifetime Imaging ◽  
Post Translational Modification

Abstract Introduction: Resistance towards CD95-mediated apoptosis is a hallmark of many different malignancies, like it is known from primary chronic lymphocytic leukemia (CLL) cells. Moreover, apoptosis mediated through CD95 is an essential mechanism to eliminate e.g. auto-reactive or virally infected cells. However, its mode of action is still not fully understood. Recently, it could be shown that palmitoylation of CD95 can influence its signaling properties. Nevertheless, the role and regulation of palmitoylated CD95 still needs to be determined. Methods and results: Previously, we could show that miR-138 and -424 are down-regulated in CLL cells. By applying luciferase reporter assays, mutations of the binding sites qRT-PCR and immunoblots after transfection of both miRs, we identified two new target genes, namely acyl protein thioesterase (APT) 1 and 2, which are under control of both miRs and thereby are significantly over-expressed in CLL cells. Interestingly, our data reveal that expression of APTs is already controlled by miRs on mRNA level. This way APT1 is regulated by miR-138 and expression of APT2 is controlled by miR-424. So far, APTs are the only enzymes known to promote de-palmitoylation. Indeed, membrane proteins are significantly less palmitoylated in CLL cells compared to normal B cells as we determined by click-chemistry, which is a non-radioactive method to determine palmitoylated proteins. Importantly, via acyl-biotin exchange assays with subsequent immunoprecipitation of CD95 and fluorescence lifetime imaging microscopy (FLIM) to Foerster resonance energy transfer (FRET) in living cells we identified APTs to directly interact with CD95 to promote de-palmitoylation, thus impairing apoptosis mediated through CD95. As proof of concept APTs were inhibited specifically by siRNAs, miRs-138/-424 or our pharmacological inhibitor Palmostatin B. Thereby we could restore CD95-mediated apoptosis in CLL cells and other cancers, pointing to a central regulatory role of APTs in CD95 apoptosis. Conclusion: The identification of the de-palmitoylation reaction of CD95 by APTs as a miRNA target provides a novel molecular mechanism how malignant cells escape from CD95-mediated apoptosis. Here, we introduce palmitoylation as a novel post-translational modification in CLL. In light of global palmitoylome studies, which show that potentially palmitoylated proteins are involved in all central cellular processes, such as protein transport, survival, migration, apoptosis and B-cell receptor signaling, this emphasizes the importance of palmitoylation and might put it on par with modifications like phosphorylation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Neutrophils Exhibit Rapid Agonist-induced Increases in Protein-associatedO-GlcNAc

2004 ◽  
Vol 279 (44) ◽  
pp. 45759-45765 ◽  
Author(s):  
Zachary T. Kneass ◽  
Richard B. Marchase
Keyword(s):  
Signal Transduction ◽  
High Performance ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Exogenous Substrate ◽  
Short Term Exposure ◽  
Hexosamine Biosynthesis ◽  
Pre Treatment ◽  
Glcnac Transferase ◽  
Induced Signal

A variety of cytoplasmic and nuclear proteins can be modified on serine and threonine residues byO-linked β-N-acetylglucosamine (O-GlcNAc), although the effects of this modification on protein and cellular functions are not completely defined. The sugar donor for theO-GlcNAc transferase that catalyzes this post-translational modification is UDP-N-acetylglucosamine (UDP-GlcNAc), a product of the hexosamine biosynthesis pathway (HBP). Here, the dynamics of theO-GlcNAc modification are examined in the physiological context of agonist-induced signal transduction using neutrophils. Formylated Met-Leu-Phe (fMLF) is shown to stimulate a rapid and transient increase in proteinO-GlcNAcylation in both immunoblot and immunofluorescence imaging assays usingO-GlcNAc-specific antibodies. In high performance liquid chromatography analyses of HBP metabolic activity, short term exposure to an exogenous substrate of the HBP, glucosamine (GlcNH2), leads to increased GlcNH26-phosphate and then UDP-GlcNAc levels. The GlcNH2treatments also increaseO-GlcNAcylation and augment the aforementioned fMLF-associated increase. In functional assays, GlcNH2pre-treatment selectively augments fMLF-induced chemotaxis but has little effect on respiratory burst activity. Furthermore, augmenting levels ofO-GlcNAc in the absence of agonist is sufficient to stimulate chemotaxis. These data demonstrate that neutrophils possess a functionally significantO-GlcNAcylation pathway that is robustly induced by stimulation with agonist. We propose thatO-GlcNAcylation plays an important role in rapid and dynamic neutrophil signal transduction, especially with respect to chemotaxis.

Polymorphisms Of Human Leukocyte Antigen-G Gene and Clinical Outcome Of Patients With Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4151-4151
Author(s):  
Gabriela Klimkiewicz-Wojciechowska ◽  
Olga Grzybowska-Izydorczyk ◽  
Maciej Borowiec ◽  
Krystyna Wyka ◽  
Marta Chmielewska ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Cell ◽  
Immune Escape ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Risk Groups ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Strong Linkage Disequilibrium ◽  
Cell Functions

Abstract Introduction The human leucocyte antigen-G (HLA-G) is a nonclassical class Ib molecule that suppresses various immune cell functions and may contribute to immune escape and cancer development. HLA-G polymorphisms, especially HLA-G-725(C/G/T) 5’URR and HLA-G 14bp del/ins 3’UTR, might influence the expression of HLA-G transcript and protein, and in consequence, affect the biological features of HLA-G. Therefore, we investigated whether these two polymorphisms, which seem to be functionally relevant, may play a role in susceptibility to chronic lymphocytic leukemia (CLL) and a clinical course of the disease. So far, no studies have reported any potentially impact of HLA-G polymorphisms on lymphoid neoplasms. Methods HLA-G725(C/G/T) 5’URR and HLA-G 14bp del/ins 3’UTR polymorphisms were genotyped in 167 previously untreated patients with CLL. The control group consisted of 98 randomly selected blood donors. Results Strong linkage disequilibrium between HLA-G-725(C/G/T) and HLA-G 14 bp del/ins was observed (D’=1.0 and r2=0.2). Six distinct haplotypes, including G/del, C/del, T/del, G/ins, C/ins, T/ins were found in the CLL patients. Among the controls only five haplotypes were found due to the T/ins haplotype not being observed. The probability of the occurrence of G/ins and T/ins haplotypes was higher in the CLL than in the controls (p= 0.01). The analysis of the prognostic significance of diplotypes, as well as the previously reported correlations between HLA-G genotypes and HLA-G expression in vitro and in vivo, allowed us to identify the HLA-G diplotype-based risk groups. The low-risk (LR) group comprised CC/del-del, CC/del-ins and CC/ins-ins diplotypes, and the high risk (HR) group included GG/del-del, GG/del-ins, GG/ins-ins, GC/del-del, GC/del-ins, GC/ins-ins, TT/del-del, TT/del-ins, TT/ins-ins and CT/del-ins diplotypes. The patients carrying LR diplotypes presented a higher 3-year treatment-free survival (TFS) (56.7%, 95% CI 47-66) than those with HR diplotypes (38.6%, 95% CI 27-52; p= 0.005). Additionally in the group of mutated IGHV patients, subjects carrying LR diplotypes presented a higher probability of 3-year TFS than those with HR diplotypes (68.5% vs 43.2%; p= 0.04). In regard to overall survival (OS), the estimated 5-year OS rates were 95.6% (95% CI 89-98) and 74.2% (95% CI 57-86) in the LR and HR group respectively (p= 0.005). Moreover, among the unmutated IGHV patients, those carrying LR diplotypes had a better 5-year OS compared to the patients with HR diplotypes (87.1% vs 71%; p= 0.02). Multivariate analysis demonstrated the IGHV mutation status (p= 0.005) and HLA-G diplotype-based risk groups (p= 0.01) to be independent factors predicting OS. Conclusions The results suggest the potential role of HLA-G and its polymorphisms in CLL. The inherited ability of the host to increase expression of the HLA-G antigen might contribute to the escape of CLL cells of the immuno-surveillance of the host and in turn to disease progression and the worse outcome for patients with CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dual functionality of O -GlcNAc transferase is required for Drosophila development

Open Biology ◽  
2015 ◽  
Vol 5 (12) ◽  
pp. 150234 ◽  
Author(s):  
Daniel Mariappa ◽  
Xiaowei Zheng ◽  
Marianne Schimpl ◽  
Olawale Raimi ◽  
Andrew T. Ferenbach ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rational Design ◽  
Catalytic Domain ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Tetratricopeptide Repeats ◽  
Sex Combs ◽  
Glcnac Transferase ◽  
Activity Dependent

Post-translational modification of intracellular proteins with O -linked N -acetylglucosamine ( O -GlcNAc) catalysed by O -GlcNAc transferase (OGT) has been linked to regulation of diverse cellular functions. OGT possesses a C-terminal glycosyltransferase catalytic domain and N-terminal tetratricopeptide repeats that are implicated in protein–protein interactions. Drosophila OGT ( Dm OGT) is encoded by super sex combs ( sxc ), mutants of which are pupal lethal. However, it is not clear if this phenotype is caused by reduction of O -GlcNAcylation. Here we use a genetic approach to demonstrate that post-pupal Drosophila development can proceed with negligible OGT catalysis, while early embryonic development is OGT activity-dependent. Structural and enzymatic comparison between human OGT (hOGT) and Dm OGT informed the rational design of Dm OGT point mutants with a range of reduced catalytic activities. Strikingly, a severely hypomorphic OGT mutant complements sxc pupal lethality. However, the hypomorphic OGT mutant-rescued progeny do not produce F2 adults, because a set of Hox genes is de-repressed in F2 embryos, resulting in homeotic phenotypes. Thus, OGT catalytic activity is required up to late pupal stages, while further development proceeds with severely reduced OGT activity.

scholarly journals IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1899
Author(s):  
Selcen Öztürk ◽  
Verena Kalter ◽  
Philipp M. Roessner ◽  
Murat Sunbul ◽  
Martina Seiffert
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mouse Model ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Immune Escape ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Leukemia Development

Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.

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