National Repository of Grey Literature 35 records found  previous11 - 20nextend  jump to record: Search took 0.00 seconds. 
Identification and Characterization of Genetic Aberrations in Acute Childhood Leukemia
Lukeš, Julius ; Kubričanová Žaliová, Markéta (advisor) ; Machová Poláková, Kateřina (referee) ; Živný, Jan (referee)
Childhood acute leukemias are genetically complex disorders, with recurrent or random aberrations found in most patients. Their proper functional characterization is crucial for understanding the role they play in the process of leukemogenesis. We aimed to identify and characterize the genetic background of two leukemic entities. The transient myeloproliferative disorder (TMD) is a preleukemic condition that occurs in 10% of newborns with Down syndrome. Trisomy 21 together with in-utero gained mutations in the GATA1 gene are essential in TMD and represent an ideal "multi-hit" model to study leukemogenesis. We investigated an alternative pathogenic mechanism enabling TMD development in a confirmed absence of trisomy 21. Novel deletions in the GATA1 and JAK1 genes were described as potential drivers of this TMD. The deletion D65_C228 in GATA1 results in the expression of an aberrant isoform, which is predicted to lose transactivation potential and, more importantly, to partially lose the ability of recognizing physiological DNA binding sites, possibly triggering TMD alone. Our thorough characterization of JAK1 F636del questions its role in TMD development. Analysis of JAK/STAT signaling suggested decrease of kinase activity upon F636 loss. Cells harboring the aberrant JAK1 did not obtain cytokine-...
Role of the oncogenic microRNAs miR-17-92 and miR-155 in the regulation of hematopoietic differentiation and leukemogenesis
Pospíšil, Vít ; Stopka, Tomáš (advisor) ; Pospíšek, Martin (referee) ; Machová Poláková, Kateřina (referee)
(English version): Hematopoietic differentiation is highly ordered multistep process, where generation of terminal blood cells is dependent upon coordinated regulation of gene expression by key regulators: transcription factors and mikroRNAs. PU.1 (Sfpi1) is a versatile hematopoetic transcription factor required for the proper generation of both myeloid and lymphoid lineages. MikroRNAs represent a novel class of ~22 nucleotide long non-coding posttranscriptional regulators that inhibit expression of genes by blocking protein translation or by mRNA degradation. In this PhD thesis I present research data documenting novel mechanisms of regulation and function of two oncogenic mikroRNAs, miR-17-92 cluster and miR-155 and myeloid transcriptional factors PU.1 upon macrophage differentiation of myeloid progenitors. The miR-17-92 cluster (Oncomir1) encodes seven related mikroRNAs that regulate cell proliferation, apoptosis and development and is overexpressed in number of malignancies including myeloid leukemia. Presented PhD thesis documents novel macrophage specific regulatory mechanisms involving the oncogenic cluster miR-17-92. Using transgenic PU.1-/- myeloid progenitors we show that upon macrophage differentiation, the transcription factor PU.1 induces the secondary determinant, the transcription...
The role of transcription factors PU.1 a GATA-1 during leukemia differentiation.
Burda, Pavel ; Stopka, Tomáš (advisor) ; Kořínek, Vladimír (referee) ; Machová Poláková, Kateřina (referee)
Hematopoiesis is coordinated by a complex regulatory network of transcription factors among them PU.1 (Spi1, Sfpi1) and GATA-1 represent key molecules. GATA-1 and PU.1 bind each other on DNA to block each others transcriptional programs to prevent development of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells, transformed erythroid precursors that are blocked from completing the late stages of erythroid differentiation, co-express GATA-1 and PU.1 and as my and others data document, are able to respond to molecular removal (down-regulation) of PU.1 or addition (up-regulation) of GATA-1 by inducing terminal erythroid differentiation. We provide novel evidence that downregulation of GATA-1 or upregulation of PU.1 induces incompletely differentiation into cell cycle arrested monocytic-like cells. Furthermore, PU.1- dependent transcriptome is negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and Core-binding factor, beta subunit (Cbfb) that encode additional key hematopoietic transcription factors. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb that are co-occupied by PU.1 and GATA-1 in the leukemic blasts. Furthermore, transcriptional regulation of these loci by...
Mechanisms of resistance to tyrosin kinase inhibitors in treatment of patients with chronic myeloid leukemia
Polívková, Václava ; Machová Poláková, Kateřina (advisor) ; Zuna, Jan (referee) ; Bělohlávková, Petra (referee)
Mechanisms of resistance to tyrosin kinase inhibitors in treatment of patients with chronic myeloid leukemia The introduction of tyrosine kinase inhibitor (TKI) therapy represented a breakthrough in the treatment of patients with chronic myeloid leukemia (CML). Despite a high success rate of the TKI therapy, 20-30 % of patients develop resistance to the treatment. The aim of this work was to study the mechanisms, related to the mutation development in BCR-ABL1 kinase domain (KD) or in the other genes responsible for TKI resistance, using the in vitro CML models. Furthermore, the effect of interferon alpha (IFN-α) and TKI sequential therapy on the presence of clones with multidrug-resistant mutations and a role of activation the immune response in achieving the treatment response were followed. Lastly, we studied the possibility of using the measurement of gene expression of hOCT1 and ABCB1 transporters at the time of diagnosis in CML patients as a predictive marker of the imatinib treatment response. KCL-22 CML cell line cells exposed to imatinib were repeatedly able to develop BCR-ABL1 kinase domain mutations. We demonstrated the existence of de novo mutagenesis in clones derived from the KCL-22 cell line. In four clones, which can proliferate in 4µM imatinib, mutations in BCR-ABL1 KD or KRAS were...
Identification and Characterization of Genetic Aberrations in Acute Childhood Leukemia
Lukeš, Julius ; Kubričanová Žaliová, Markéta (advisor) ; Machová Poláková, Kateřina (referee) ; Živný, Jan (referee)
Childhood acute leukemias are genetically complex disorders, with recurrent or random aberrations found in most patients. Their proper functional characterization is crucial for understanding the role they play in the process of leukemogenesis. We aimed to identify and characterize the genetic background of two leukemic entities. The transient myeloproliferative disorder (TMD) is a preleukemic condition that occurs in 10% of newborns with Down syndrome. Trisomy 21 together with in-utero gained mutations in the GATA1 gene are essential in TMD and represent an ideal "multi-hit" model to study leukemogenesis. We investigated an alternative pathogenic mechanism enabling TMD development in a confirmed absence of trisomy 21. Novel deletions in the GATA1 and JAK1 genes were described as potential drivers of this TMD. The deletion D65_C228 in GATA1 results in the expression of an aberrant isoform, which is predicted to lose transactivation potential and, more importantly, to partially lose the ability of recognizing physiological DNA binding sites, possibly triggering TMD alone. Our thorough characterization of JAK1 F636del questions its role in TMD development. Analysis of JAK/STAT signaling suggested decrease of kinase activity upon F636 loss. Cells harboring the aberrant JAK1 did not obtain cytokine-...
Influence of stuttering on social acceptance of people who stutter
Machová, Kateřina ; Černá, Martina (advisor) ; Veroňková, Jitka (referee)
Stuttering is generally known in public. In the Czech enviroment is more common to examine balbutism especially from the terminological point of view. Abroad, we find also those types of researches, which aim is to find out more about the influence of stuttering on the social acceptance of people who stutter. The aim of our work is to contribute to this area of researches. Our reasearch consists of two parts: a perception test for respondents without stuttering and semi-structured interviews with people who stutter. We asked 5 stutteres, with whom both recording and unrecorded semi-structured interviews were made. Those interviews focused on their experiences with social acceptance in various spheres of life (relationships, job opportunities etc.) A perception test was created from the recordings a than played to 20 respondents without stuttering. Based on these recordings, respondents assesed the personality traits of the speakers and their social opportunities on five-point Likert scale. After that, the results of both types of research were compared and related to the previous research. The relation between the results of our research and previous researches were found in only one case out of five stutterers. In this case the symptoms of stuttering we subjectively percieved as the most severe....
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...
Epigenetic factors CTCF a SMARCA5 control expression of hematopoietic transcription factor SPI1 in cells of acute myeloid leukemia and myelodysplastic syndrome.
Dluhošová, Martina ; Stopka, Tomáš (advisor) ; Machová Poláková, Kateřina (referee) ; Kozák, Tomáš (referee)
CCCTC-binding factor (CTCF) can both activate as well as inhibit transcription by forming chromatin loops between regulatory regions and promoters. In this regard, Ctcf binding on the non-methylated DNA and its interaction with the Cohesin complex results in differential regulation of the H19/Igf2 locus. Similarly, a role for CTCF has been established in normal hematopoietic development; however its involvement, despite mutations in CTCF and Cohesin complex were identified in leukemia, remains elusive. CTCF regulates transcription dependently on DNA methylation status and can if bound block interactions of enhancers and promoters. Here, we show that in hematopietic cells CTCF binds to the imprinting control region of H19/Igf2 and found that chromatin remodeller Smarca5, which also associates with the Cohesin complex, facilitates Ctcf binding and regulatory effects. Furthermore, Smarca5 supports CTCF functionally and is needed for enhancer-blocking effect at imprinting control region. We identified new CTCF-recognized locus near hematopoietic regulator SPI1 (PU.1) in normally differentiating myeloid cells together with members of the Cohesin complex. Due to DNA methylation, CTCF binding to the SPI1 gene is reduced in AML blasts and this effect was reversible by DNA methylation inhibitor 5-azacitidine.
Experimental therapy of B-cell Non-Hodgkin's lymphonas.
Klánová, Magdalena ; Klener, Pavel (advisor) ; Machová Poláková, Kateřina (referee) ; Froňková, Eva (referee)
1 ABSTRACT B-cell non-Hodgkin lymphomas (B-NHL) represent the most common mature lymphoproliferative diseases. B-NHL arise at different stages of B-cell development and represent their malignant counterpart. Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are aggressive types of B-NHLs. Deregulation of cell cycle control, inhibition of apoptosis or abnormal DNA damage response play a key role in the pathogenesis of DLBCL and MCL. Aberrant activation of several signaling pathways that further promote survival, cell proliferation or affect the tumor microenvironment have been recently recognized. Increased understanding of the oncogenic mechanisms implicated in pathogenesis of B-NHL lead to development of novel agents that target the oncogenic drivers of distinct lymphoma subtypes. MCL is an aggressive subtype of B-NHL associated with poor prognosis. In vivo models of human MCL for experimental therapy are however scarce. We established and characterized several mouse models of human MCL by xenotransplantation of either primary cells or established cell lines into immunodeficient mice (publication no 1). We demonstrated that engrafted MCL cells displayed complex changes of gene expression profile, phenotype and sensitivity to cytotoxic agents compared to the original in vitro growing...

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