|
|
TEL/AML1, BCR/ABL and TEL/ABL Fusion genes in childhood acute lymphoblastic leukemia
Žaliová, Markéta ; Trka, Jan (advisor) ; Machová Poláková, Kateřina (referee) ; Pospíšilová, Dagmar (referee)
Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. It represents a group of clinically and biologically heterogenous malignancies that can be subclasified into several subtypes according to the presence of recurrent genetic aberrations. The typical genetic aberrations in childhood ALL are chromosomal translocation, that often result in creation of fusion genes encoding either chimeric kinases or chimeric transcription factors. These recurrent genetic aberations are aquired lesions, they are supposed to be the initial hits (that may arise even prenataly) with a causal role in the process of leukemogenesis, which is, however, in the majority of them not yet fully understood. They further represent specific markes used for the detection of leukemic cells and some of them have also prognostic significance and belong among the factors used for risk group stratification in treatment protocols. Risk group stratification and subsequent risk-adapted therapy together with introduction of new therapeutic approaches (intensive chemotherapeutic regimens involving intrathecal application, hematopoetic stem cell transplantation (HSCT), supportive therapy) account for the significant improvement of the treatment outcomes of childhood ALL in the last decades. In addition to genotype, several...
|
|
|
Genetic and epigenetic mechanisms (and their cooperation) in the leukemogenesis of acute myeloid leukemia in adults.
Šestáková, Šárka ; Šálek, Cyril (advisor) ; Vymetálková, Veronika (referee) ; Kubričanová Žaliová, Markéta (referee)
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by great heterogeneity and clonal nature. In recent years, rapidly evolving next-generation sequencing methods provided a deep insight into the mutational background of AML. It was shown that ~ 44 % of AML patients harbor mutations in genes that regulate DNA methylation. So far, many researchers have tried to evaluate the prognostic significance of DNA methylation changes in AML, however, due to a great inconsistency in these studies, none of the reported markers were implemented into clinical practice. The aim of this work was to further investigate the DNA methylation changes in AML patients with specific mutations and their prognostic effect. Next, we wanted to develop a new approach for a complex evaluation of prognostically significant DNA methylation aberrations. In our first project, we assessed the overall DNA methylation, hydroxymethylation, and gene expression in AML patients with mutations in either DNMT3A or IDH1/2 or their combinations. We discovered that each genetic aberration is connected with a distinct pattern of DNA hydroxy-/methylation changes that are not entirely reflected in altered gene expression. Patients with mutations in both genes exhibited a mixed DNA methylation profile most similar to healthy...
|
|
|
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-...
|
|
|
Genetic and epigenetic mechanisms (and their cooperation) in the leukemogenesis of acute myeloid leukemia in adults.
Šestáková, Šárka ; Šálek, Cyril (advisor) ; Vymetálková, Veronika (referee) ; Kubričanová Žaliová, Markéta (referee)
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by great heterogeneity and clonal nature. In recent years, rapidly evolving next-generation sequencing methods provided a deep insight into the mutational background of AML. It was shown that ~ 44 % of AML patients harbor mutations in genes that regulate DNA methylation. So far, many researchers have tried to evaluate the prognostic significance of DNA methylation changes in AML, however, due to a great inconsistency in these studies, none of the reported markers were implemented into clinical practice. The aim of this work was to further investigate the DNA methylation changes in AML patients with specific mutations and their prognostic effect. Next, we wanted to develop a new approach for a complex evaluation of prognostically significant DNA methylation aberrations. In our first project, we assessed the overall DNA methylation, hydroxymethylation, and gene expression in AML patients with mutations in either DNMT3A or IDH1/2 or their combinations. We discovered that each genetic aberration is connected with a distinct pattern of DNA hydroxy-/methylation changes that are not entirely reflected in altered gene expression. Patients with mutations in both genes exhibited a mixed DNA methylation profile most similar to healthy...
|
|
|
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-...
|
|
| |
|
|
TEL/AML1, BCR/ABL and TEL/ABL Fusion genes in childhood acute lymphoblastic leukemia
Žaliová, Markéta ; Trka, Jan (advisor) ; Machová Poláková, Kateřina (referee) ; Pospíšilová, Dagmar (referee)
Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. It represents a group of clinically and biologically heterogenous malignancies that can be subclasified into several subtypes according to the presence of recurrent genetic aberrations. The typical genetic aberrations in childhood ALL are chromosomal translocation, that often result in creation of fusion genes encoding either chimeric kinases or chimeric transcription factors. These recurrent genetic aberations are aquired lesions, they are supposed to be the initial hits (that may arise even prenataly) with a causal role in the process of leukemogenesis, which is, however, in the majority of them not yet fully understood. They further represent specific markes used for the detection of leukemic cells and some of them have also prognostic significance and belong among the factors used for risk group stratification in treatment protocols. Risk group stratification and subsequent risk-adapted therapy together with introduction of new therapeutic approaches (intensive chemotherapeutic regimens involving intrathecal application, hematopoetic stem cell transplantation (HSCT), supportive therapy) account for the significant improvement of the treatment outcomes of childhood ALL in the last decades. In addition to genotype, several...
|
guest ::
