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Myelodysplastic syndromes - search for the molecular basis]
Beličková, Monika ; Čermák, Jaroslav (advisor) ; Divoký, Vladimír (referee) ; Pospíšilová, Dagmar (referee)
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell disorders with ineffective hematopoiesis. It is characterized by morphological dysplasia, peripheral cytopenias affecting one or more cell lineages and an increased risk of transformation into acute myeloid leukemia (AML). The early stages of MDS can be considered a premalignant disease. The pathogenesis of MDS has not been fully explained yet, but due to the development of molecular genetic and cytogenetic methods, the origin and development of the disease is gradually being elucidated. In addition to the cytogenetic changes that are part of the prognostic system (IPSS-R), the somatic mutations found in different genes come to the forefront of interest. However, they are not routinely used in clinical practice. One of the objectives of this study was monitoring of mutations in TP53 gene in lower-risk MDS patients who generally have a good prognosis and for whom these findings have a particularly relevant prognostic significance. We investigated a total of 154 patients with lower-risk MDS, and 13% of them had a mutation. After dividing patients according to the presence of del(5q), we observed significant differences in the incidence of the mutations. The mutations were detected in 23.6% of patients with...
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The expression of TP53 gene at the mRNA level in patients with myelodysplastic syndrome
Šeborová, Karolína ; Beličková, Monika (advisor) ; Španielová, Hana (referee)
Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases characterized by ineffective hematopoiesis which is caused by damage of differentiation of pluripotent haematopoietic stem cells. TP53 gene mutations are identified approximately in 10% of MDS and represent a negative prognostic factor. Altered TP53 gene expression may have similar effect as the mutation. Mutations or deregulated expression of this gene have an impact on many cellular processes including apoptosis, DNA repair, cell growth and angiogenesis. In this work, the expression mRNA levels of genes involved in p53 signalling pathway were studied in CD34+ pluripotent haematopoietic cells from bone marrow of patients with low- risk MDS. MDS patients showed increased expression of genes involved in apoptosis induction, regulation of cell cycle and DNA repair (BAX, BBC3, CCNE1, CDC25A, CDKN1A, FAS, GADD45A) as compared to healthy subjects. The patients with TP53 mutation had decreased expression of apoptotic genes (BAX, PIDD, TRAF2) and increased gene expression of apoptotic inhibitor (BCL2A1), indicating a reduced activity of apoptotic pathways and that way the pathological cell clone may gain a growth advantage. Deregulation of 21 genes (BAX, BBC3, EGR1, KAT2B, MDM2 etc.) was observed in patients with del (5q) compared to...
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Monitoring of blood counts parameters during the therapy in patients with myelodysplastic syndrome
Sochorová, Lenka ; Fátorová, Ilona (advisor) ; Vrbacký, Filip (referee)
Blood counts belongs among basic examination methods in hematology laboratory. It is used to determine the basic parameters of leukocytes, erythrocytes, hemoglobin, hematocrit and platelets. The goal of study was to determine which blood counts have changed during the treatment of patients with myelodysplastic syndrome using immunomodulatory drug lenalidomide. Analysis of blood samples were performed on the Sysmex XE-5000. The selected blood counts parameters were evaluated in two periods - before the beginning of the treatment and during the treatment. The final blood counts showed increasing concentrations of hemoglobin and decreasing platelet values; other blood count parameters have not changed significantly. The evaluated blood counts changes could be used to determine the efficiency of the treatment and the transfusion therapy could be stopped based on these results.
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DNA methylation in haematological malignancies
Šeborová, Karolína ; Beličková, Monika (advisor) ; Vopálenský, Václav (referee)
DNA methylation is one of the most common epigenetics modifications, during which a methyl group from the donor molecule S-adenosyl-L-methionine is transferred to the 5'position of the cytosine ring to create 5-methylcytosine. This reaction is catalyzed by DNA methyltransferases. Epigenetics modification plays an important role in the regulation of the transcription, genomic imprinting, X-chromosome inactivation and the development of the organism. This role in the regulation of transcription is important for the cancer. Especially the aberrant forms, like hypermethylation, which leads to transcriptional silencing of the tumor suppressing genes leading to the tumor progression, or hypomethylation causing genomic instability. Key words: DNA methylation, demethylating drugs, haematological malignancies, methods of detection, myelodysplastic syndrome
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Role of 5-azacytidine in therapy of myelodysplastic syndrome
Machalová, Veronika ; Hodný, Zdeněk (advisor) ; Indrová, Marie (referee)
The myelodysplastic syndrome (MDS) is a group of hematopoietic clonal disorders resulting in the inefficient production of myeloid lineage blood cells, with the prevalence of patients older than 65 years. One of the possible treatment options for MDS is 5- azacytidine and 5-aza-2'-deoxycytidine therapy. These compounds have been shown to cause the induction of cell-cycle arrest, cell differentiation and/or apoptosis. The in vitro experiments with 5-aza-2'-deoxycytidine indicated that this compound causes the premature cellular senescence, a state of the irreversible cell-cycle arrest. We have asked, whether 5-azacytidine, as a molecule with similar structure, is capable of causing the same effect. This treatment strategy could be beneficial in case that the negative pro- inflammatory effect of senescent cells on their surroundings can be nullified. In this thesis we have shown that 5-azacytidine induces DNA damage response, which is described as a fundamental event for the onset of the cell senescence. We tested 5- azacytidine treated HeLa cells for several markers of the cell senescence - the increase of the β-galactosidase activity, the PML and PML nuclear bodies and the formation of persistent DNA damage signaling lesions - albeit all these markers were positive, it was the very low increase in...
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