Aberrant glycosylation of glycoproteins has been linked with various pathologies. Therefore, understanding the relationship between aberrant glycosylation patterns and the onset and progression of the disease is an important research goal that may provide insights into cancer diagnosis and new therapy development. In this study, we use a surface plasmon resonance imaging biosensor and a lectin array to investigate aberrant glycosylation patterns associated with oncohematological disease-myelodysplastic syndromes (MDS). In particular, we detected the interaction between the lectins and glycoproteins present in the blood plasma of patients (three MDS subgroups with different risks of progression to acute myeloid leukemia (AML) and AML patients) and healthy controls. The interaction with lectins from Aleuria aurantia (AAL) and Erythrina cristagalli was more pronounced for plasma samples of the MDS and AML patients, and there was a significant difference between the sensor response to the interaction of AAL with blood plasma from low and medium-risk MDS patients and healthy controls. Our data also suggest that progression from MDS to AML is accompanied by sialylation of glycoproteins and increased levels of truncated O-glycans and that the number of lectins that allow discriminating different stages of disease increases as the disease progresses.

• MeSH
• akutní myeloidní leukemie * MeSH
• biosenzitivní techniky * MeSH
• glykoproteiny metabolismus   MeSH
• glykosylace MeSH
• krevní plazma metabolismus   MeSH
• lektiny MeSH
• lidé MeSH
• myelodysplastické syndromy * terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glykoproteiny MeSH
• lektiny MeSH

Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (SBSN). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed SBSN is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of SBSN to various human diseases, including cancer, attract research interest. The association of SBSN expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that SBSN may play a role in human tumourigenesis. Three SBSN isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about SBSN, we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of SBSN in both physiology and pathology.

• Klíčová slova
• MAPK signalling, cancer resistance, cancer stem-like cells, immunity, interferon, suprabasin,
• MeSH
• diferenciační antigeny * genetika   metabolismus   MeSH
• karcinogeneze * genetika   metabolismus   MeSH
• lidé MeSH
• nádorové proteiny * genetika   metabolismus   MeSH
• nádory * genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• diferenciační antigeny * MeSH
• nádorové proteiny * MeSH
• SBSN protein, human MeSH Prohlížeč

Myelodysplastic syndromes (MDS) are preleukemic disorders characterized by clonal growth of mutant hematopoietic stem and progenitor cells. MDS are associated with proinflammatory signaling, dysregulated immune response, and cell death in the bone marrow (BM). Aging, autoinflammation and autoimmunity are crucial features of disease progression, concordant with promoting growth of malignant clones and accumulation of mutations. Suprabasin (SBSN), a recently proposed proto-oncogene of unknown function, physiologically expressed in stratified epithelia, is associated with poor prognosis of several human malignancies. Here, we showed that SBSN is expressed in the BM by myeloid cell subpopulations, including myeloid-derived suppressor cells, and is secreted into BM plasma and peripheral blood of MDS patients. The highest expression of SBSN was present in a patient group with poor prognosis. SBSN levels in the BM correlated positively with blast percentage and negatively with CCL2 chemokine levels and lymphocyte count. In vitro treatment of leukemic cells with interferon-gamma and demethylating agent 5-azacytidine (5-AC) induced SBSN expression. This indicated that aberrant cytokine levels in the BM and epigenetic landscape modifications in MDS patients may underlie ectopic expression of SBSN. Our findings suggest SBSN as a candidate biomarker of high-risk MDS with a possible role in disease progression and therapy resistance.

• Klíčová slova
• 5-azacytidine, MDS, MDSCs, biomarker, suprabasin,
• MeSH
• azacytidin farmakologie   MeSH
• biologické markery krev   metabolismus   MeSH
• chemokin CCL2 metabolismus   MeSH
• diferenciační antigeny krev   genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• interferon gama farmakologie   MeSH
• kompartmentace buňky účinky léků   MeSH
• kostní dřeň metabolismus   MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• myelodysplastické syndromy krev   metabolismus   MeSH
• myeloidní buňky účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny krev   genetika   metabolismus   MeSH
• počet lymfocytů MeSH
• prognóza MeSH
• protoonkogen Mas MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azacytidin MeSH
• biologické markery MeSH
• chemokin CCL2 MeSH
• diferenciační antigeny MeSH
• interferon gama MeSH
• MAS1 protein, human MeSH Prohlížeč
• messenger RNA MeSH
• nádorové proteiny MeSH
• protoonkogen Mas MeSH
• SBSN protein, human MeSH Prohlížeč

Wild type mitochondrial isocitrate dehydrogenase (IDH2) was previously reported to produce oncometabolite 2-hydroxyglutarate (2HG). Besides, mitochondrial deacetylase SIRT3 has been shown to regulate the oxidative function of IDH2. However, regulation of 2HG formation by SIRT3-mediated deacetylation was not investigated yet. We aimed to study mitochondrial IDH2 function in response to acetylation and deacetylation, and focus specifically on 2HG production by IDH2. We used acetylation surrogate mutant of IDH2 K413Q and assayed enzyme kinetics of oxidative decarboxylation of isocitrate, 2HG production by the enzyme, and 2HG production in cells. The purified IDH2 K413Q exhibited lower oxidative reaction rates than IDH2 WT. 2HG production by IDH2 K413Q was largely diminished at the enzymatic and cellular level, and knockdown of SIRT3 also inhibited 2HG production by IDH2. Contrary, the expression of putative mitochondrial acetylase GCN5L likely does not target IDH2. Using mass spectroscopy, we further identified lysine residues within IDH2, which are the substrates of SIRT3. In summary, we demonstrate that 2HG levels arise from non-mutant IDH2 reductive function and decrease with increasing acetylation level. The newly identified lysine residues might apply in regulation of IDH2 function in response to metabolic perturbations occurring in cancer cells, such as glucose-free conditions.

• MeSH
• acetylace MeSH
• glutaráty metabolismus   MeSH
• isocitrátdehydrogenasa genetika   metabolismus   MeSH
• isocitráty chemie   MeSH
• lidé MeSH
• mitochondrie metabolismus   MeSH
• nádorové buněčné linie MeSH
• NADP metabolismus   MeSH
• oxidace-redukce MeSH
• proteiny nervové tkáně metabolismus   MeSH
• sirtuin 3 metabolismus   MeSH
• umlčování genů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alpha-hydroxyglutarate MeSH Prohlížeč
• BLOC1S1 protein, human MeSH Prohlížeč
• glutaráty MeSH
• IDH2 protein, human MeSH Prohlížeč
• isocitrátdehydrogenasa MeSH
• isocitráty MeSH
• isocitric acid MeSH Prohlížeč
• NADP MeSH
• proteiny nervové tkáně MeSH
• SIRT3 protein, human MeSH Prohlížeč
• sirtuin 3 MeSH