|
|
Regulatory mechanisms of WNT signalling
Pospíchalová, Vendula ; Kořínek, Vladimír (advisor) ; Trka, Jan (referee) ; Bryja, Josef (referee)
AB T mu hom dise β sign mu liga stab tran sign T the focu disc cate of t cell targ the inte con sec I sign BSTRACT The Wnt si lticellular o meostasis. A eases, most β-catenin is nalling). In ltiprotein c ands when t bilized and nscription f nalling is tig This thesis knowledge uses on seq cusses the enin signall the Wnt pa ls of intest geted mous thesis des eraction wit nditional Hi retory cell t In conclusi nalling path T ignalling pa organisms Accordingly notably can s a central m n unstimula complex and they engage d transloca factors and ghtly regula is based on e of the reg quential po positive ro ling outcom athway whic tinal epithe e strains th scribes unp th members ic1 deletion types and en ion, our fin hway in dev athway is o ensuring s y, mutations ncer. mediator of ated cells d degraded e their recep tes to the to drive th ated at vario n four origin gulation of sttranslation ole of nucle me. The third ch reduces lium. Final at enable st ublished da s of the Wn n in the inte nhanced tum ndings contr velopment an one of the m successful s in the pat f canonical W β-catenin d in the pro ptors, degrad nucleus t he transcrip ous levels b nal articles f the Wnt s nal process ear protein d study repo the levels o lly, the las tudying the ata on the nt pathway, estinal epith mourigenesi ributed to t...
|
|
| |
|
|
Molecular genetic alterations in acute myeloid leukemia.
Marková, Jana ; Schwarz, Jiří (advisor) ; Trka, Jan (referee) ; Žák, Pavel (referee)
Cytogenetic and molecular genetic analyses are necessary for precise assessment of diagnosis, prognosis and treatment of patients with AML. The karyotypic analysis allows the distribution of patients into the basic risk groups, while the methods of molecular biology offer further possibilities to stratify patients within particular risk subgroups. Moreover, using quantitative PCR, they enable to follow the course of minimal residual disease (MRD) and foresee the eventual relapse of the disease. The aim of this thesis was to analyse the prognostic impact of new molecular markers in patients with AML, particularly in those with favourable (acute promyelocytic leukemia (APL), CBF-AML) and intermediate (influence of FLT3 mutations and others) cytogenetic profiles. The presence of fusion genes PML/RARα, AML1/ETO and CBFβ/MYH11 was tested by qualitative PCR. Patients harbouring fusion genes AML1/ETO or CBFβ/MYH11 (CBF-AML) were further analysed using either sequencing or restriction digest analysis, for the presence of C-KIT, K-RAS, N-RAS and FLT3 mutations. Patients with intermediate cytogenetic risk were tested for presence of internal tandem duplications of FLT3 (FLT3/ITD), mutations in tyrosine kinase domain of FLT3 (FLT3/TKD), DNMT3A and ASXL1 mutations. Cases with a complex karyotype were screened...
|
|
|
Transcription factor PU.1 is a target of 5-azacitidine during differentiation therapy of myelodysplastic syndrome
Čuřík, Nikola ; Stopka, Tomáš (advisor) ; Kleibl, Zdeněk (referee) ; Trka, Jan (referee)
PU.1 is a key hematopoietic transcription factor. Knock-out of PU.1 in mouse is embryonic lethal due to complete depletion or several disruption of differentiation of multiple blood cell lineages. Low level of PU.1 and the disruption of its regulation are associated in vivo with acute myeloid leukemia and other hematologic malignancies. Myelodysplastic syndrome (MDS) is hematopoietic stem cell disorder with extremely heterogeneous features and outcome. It is characterized by improper differentiation of blood cells resulting in loss of function, dysplasia and blasts accumulation in bone marrow. About one third of MDS cases transforms into AML. MDS is also characterized by silencing of gene expression caused by aberrant DNA hypermethylation. Using DNA Methyltransferase inhibitors (DNMTi) such as 5-azacitidine (AZA) has good clinical results for the MDS patients with higher risk of disease. Indeed, AZA became standard therapy of high risk MDS in recent years. Nonetheless, our understanding of molecular mechanisms of AZA remains incomplete. This PhD thesis reports about the role of transcription factor PU.1 in MDS. We found that significant subset of high risk MDS patients express low level of PU.1 due to DNA hypermethylation of PU.1 upstream regulatory element (URE). We also found significant...
|
|
|
Molecular mechanisms of Diamond-Blackfan anemia
Handrková, Helena ; Petrák, Jiří (advisor) ; Šebela, Marek (referee) ; Trka, Jan (referee)
Diamond-Blackfan anemia (DBA) is a rare congenital syndrome that presents with ane- mia and selective deficiency of erythroid precursors, while other blood lineages are usu- ally unaffected. Approximately half of the patients display additional somatic anoma- lies and growth retardation. The therapy is mostly symptomatic and is dominated by corticosteroids, other modalities include regular blood transfusions or hematopoietic stem cell transplantation. At the beginning of this work, only two DBA causal genes were known, RPS19 and RPS24, being mutated in approximately 1/4 of all DBA patients. The goals of this work were to study the consequences of the known DBA causal mutations on cellular level and to find novel DBA causal genes. To date, over a half of DBA patients have been reported to carry a mutation in one of nine known DBA causal genes, including RPS17, RPL11 and RPL5, that are reported in this dissertation. All confirmed DBA causal genes encode for ribosomal proteins (RPs) that were essential for ribosome assembly. We further hypothesized a non- ribosomal protein participating in this process might be involved in DBA pathogenesis, too. In one DBA patient, we identified a rare sequence variant in one such candidate, a protein arginine methyltransferase 3 (PRMT3). We reported that the patient PRMT3...
|
|
| |
|
| |
|
| |
|
| |
|
|
Molecular genetic alterations in acute myeloid leukemia.
Marková, Jana ; Schwarz, Jiří (advisor) ; Trka, Jan (referee) ; Žák, Pavel (referee)
Cytogenetic and molecular genetic analyses are necessary for precise assessment of diagnosis, prognosis and treatment of patients with AML. The karyotypic analysis allows the distribution of patients into the basic risk groups, while the methods of molecular biology offer further possibilities to stratify patients within particular risk subgroups. Moreover, using quantitative PCR, they enable to follow the course of minimal residual disease (MRD) and foresee the eventual relapse of the disease. The aim of this thesis was to analyse the prognostic impact of new molecular markers in patients with AML, particularly in those with favourable (acute promyelocytic leukemia (APL), CBF-AML) and intermediate (influence of FLT3 mutations and others) cytogenetic profiles. The presence of fusion genes PML/RARα, AML1/ETO and CBFβ/MYH11 was tested by qualitative PCR. Patients harbouring fusion genes AML1/ETO or CBFβ/MYH11 (CBF-AML) were further analysed using either sequencing or restriction digest analysis, for the presence of C-KIT, K-RAS, N-RAS and FLT3 mutations. Patients with intermediate cytogenetic risk were tested for presence of internal tandem duplications of FLT3 (FLT3/ITD), mutations in tyrosine kinase domain of FLT3 (FLT3/TKD), DNMT3A and ASXL1 mutations. Cases with a complex karyotype were screened...
|
guest ::
