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The role of HOXA9 gene in leukemogenesis
Rejlová, Kateřina ; Starková, Júlia (advisor) ; Fraiberk, Martin (referee)
The evolutionarily conserved family of homeobox genes plays an important role in the development of the anterior-posterior body axis of vertebrates. These genes significantly affect hematopoiesis, the development of blood cells. Extensive studies on homeobox genes in normal hematopoiesis confirmed their role also in leukemogenesis. Since the neoplastic transformation of blood cells, i.e. leukemia, is the most frequent malignancy in children, it has become a major subject of research for many scientists. Precisely in what stage of the malignant transformation the homeobox genes take part has not been shown yet. Neither is it known whether HOX genes are crucial in pathogenesis or whether their deregulation is only a side effect of leukemogenesis. The most studied homeobox gene in leukemogenesis is the HOXA9 gene, which showed correlation with the prognosis of patients with certain leukemias. Many studies describe the effect of HOXA9 in leukemic cell transformation, suggesting this gene could be a promising future target in leukemia therapy. This work is focused on the HOXA9 gene and its association with leukemic transformation of blood cells.
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Regulation of HOX genes expression in hematopoesis and leukemogenesis
Rejlová, Kateřina ; Starková, Júlia (advisor) ; Machová Poláková, Kateřina (referee) ; Fišerová, Jindřiška (referee)
HOX gene expression is tightly regulated during hematopoiesis and it is gradually decreased during the differentiation of hematopoietic cells. By contrast in case of leukemic blasts the expression of HOX genes is often disrupted and dysregulated. Especially in acute myeloid leukemia (AML) different expression of HOX genes was described between different subtypes classified according to cytogenetics and molecular genetics. In this study, the cohort of childhood AML patients were screened for HOX gene expression and based on these valuesdivided into five clusters using unsupervised hierarchical clustering characterized mainly by presence or absence of the typical molecular aberrations. HOX gene expression was also tested in the healthy counterpart of hematologic cells equivalent to the particular morphological stages of leukemic cells. Based on these results, HOX gene expression directly or indirectly participate in leukemogenesis and it not only copies the developmental/morphological stage in which the hematopoietic cell was stopped during differentiation. It this thesis/study it was concluded that the HOX gene expression is dependent on the presence of specific molecular aberration. In the second part of our study, we investigated the HOX gene transcription regulation in AML patients with PML-RARα...
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Regulation of DLX1 gene expression through AP-1 binding site
Rejlová, Kateřina ; Starková, Júlia (advisor) ; Machová Poláková, Kateřina (referee)
Regulation of expression DLX1 gene, whose elevated levels are detected in patients with acute myeloid leukemia with FLT3-ITD mutations, is not still completely explored topic. The first aim of this study was to determine which selected signaling pathways regulate gene expression of DLX1. ERK a JNK pathways were selected by using qRT-PCR and western blot. These pathways cause activation of the transcription factor AP-1 subunits, the AP-1 putative promoter binding site was identified also in the promoter of the DLX1 gene. The second aim of this study was to test the hypothesis on the regulation of gene expression of DLX1 (via ERK/JNK pathway) through AP-1 binding site on the promoter. Dual luciferase assay using luminescent luciferase activity was performed to test this hypothesis. Gene of the luciferase is contained in the used luciferase vector. The short and the long part of the DLX1 promoter (around AP-1 site) were inserted before the gene of the luciferase in the constructs used in this method. The results of this study indicate that the regulation of gene expression through AP-1 promoter binding site is important but not sufficient part of the regulatory cascade running through ERK and JNK pathway. There must be another transcription factors activated by ERK1/2 kinase which are probably also involved in...
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The role of HOXA9 gene in leukemogenesis
Rejlová, Kateřina ; Starková, Júlia (advisor) ; Fraiberk, Martin (referee)
The evolutionarily conserved family of homeobox genes plays an important role in the development of the anterior-posterior body axis of vertebrates. These genes significantly affect hematopoiesis, the development of blood cells. Extensive studies on homeobox genes in normal hematopoiesis confirmed their role also in leukemogenesis. Since the neoplastic transformation of blood cells, i.e. leukemia, is the most frequent malignancy in children, it has become a major subject of research for many scientists. Precisely in what stage of the malignant transformation the homeobox genes take part has not been shown yet. Neither is it known whether HOX genes are crucial in pathogenesis or whether their deregulation is only a side effect of leukemogenesis. The most studied homeobox gene in leukemogenesis is the HOXA9 gene, which showed correlation with the prognosis of patients with certain leukemias. Many studies describe the effect of HOXA9 in leukemic cell transformation, suggesting this gene could be a promising future target in leukemia therapy. This work is focused on the HOXA9 gene and its association with leukemic transformation of blood cells.
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