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Myeloid lineage involvement in BCR/ABL-positive acute lymphoblastic leukaemia
Hovorková, Lenka ; Zuna, Jan (advisor) ; Mikyšková, Romana (referee)
The Philadelphia chromosome has been discovered in 1960. This chromosomal aberration was mistakenly associated only with chronic myeloid leukaemia (CML) for decade. However, this type of translocation including chromosomes 9 and 22 was found in patients with different type of neoplasia - acute lymphoblastic leukaemia (ALL). Different lineage involvement has been found in these two types of leukaemia. Whereas in Ph-positive ALL, the Philadelphia chromosome is restricted to the lymphoid lineage, in CML patients mostly myeloid cells are those being Ph-positive. Hence it seems quite trivial to distinguish between ALL and CML. But there is a phase of CML called lymphoid blast crisis which is indistinguishable from ALL. The possibility of distinguishing between CML in lymphoid blast crisis and ALL would inhere in determining myeloid lineage involvement. Actually it had been shown that some patients with Ph+ ALL have involved also a myeloid lineage. Different types of treating protocols are used in CML and ALL. In addition, prognoses for both types of leukaemia are different. Thus it is crucial to distinguish between this two disorders and revealing of any difference can impact the treatment outcome of above mentioned malignancies. Detection of minimal residual disease according to involvement of myeloid or CD34+...
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Leukaemias with BCR/ABL fusion gene.
Hovorková, Lenka ; Zuna, Jan (advisor) ; Zemanová, Karla (referee)
Philadelphia (Ph) chromosome, as a result of reciprocal translocation, is in majority of cases connected to two types of leukaemia - chronic myelogenous (CML) and acute lymphoblastic (ALL). The translocation occurs within large intronic sequences of BCR and ABL genes. The breakpoints are specific for individual patient and may be used as a target for monitoring of leukemic burden (MRD, minimal residual disease) during the treatment. In general, MRD is an important prognostic factor, which influences the treatment intensity. Two standardized methods are currently used for its monitoring. The first one is based on the detection of clonal specific Immunoglobulin and/or T-cell receptor genes rearrangements (and thus cannot be used for CML cases) at the DNA level, the second one utilizes detection of the BCR/ABL fusion gene at the mRNA level. Our aim was to optimize and standardize the process to find individual patient breakpoints on Ph chromosome and to use it for MRD quantification. We found the breakpoint in 80 % cases. The MRD data from 15 patients obtained by our method were compared to the levels obtained by standard methods (Ig/TCR and BCR/ABL transcript quantification). In all but 1 patient we found significant discrepancies, raising the questions about leukemic origin and the most accurate method for...
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Leukaemia associated immunophenotype in childhood acute leukaemias and its development during the course of disease
Podolská, Tereza ; Fišer, Karel (advisor) ; Drbal, Karel (referee)
Acute lymphoblastic leukaemia (ALL) is the most frequent childhood malignancy. One of the recent improvements in ALL treatment was the introduction of minimal residual disease (MRD) monitoring that enables risk stratification based treatment adaptation. The same MRD monitoring helps to choose relapse treatment, to guide indication for stem cell transplantation (SCT) and allows for a more personalized management of patients undergoing SCT. One of the main routes of MRD levels detection is characterisation of leukemic blasts using flow cytometry. However, flow cytometry is limited by its mainly manual expertise-based analysis. Such analysis is subjective and clearly insufficient for current complex data. While new computational tools are available for multidimensional flow cytometry data, there is an urgent need to test and adapt them for the use in clinical environment. The goal of this thesis is to detect immunophenotypes associated with leukaemia and their development by leveraging machine-assisted analysis of a set of diagnostic files selected based on information about more than three hundred thousand of multiparameter flow cytometry datasets. Advanced bioinformatic tools will help to detect blast and healthy haematopoietic populations, to derive their immunophenotypes and to identify individual...
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Leukaemias with BCR/ABL fusion gene.
Hovorková, Lenka ; Zuna, Jan (advisor) ; Zemanová, Karla (referee)
Philadelphia (Ph) chromosome, as a result of reciprocal translocation, is in majority of cases connected to two types of leukaemia - chronic myelogenous (CML) and acute lymphoblastic (ALL). The translocation occurs within large intronic sequences of BCR and ABL genes. The breakpoints are specific for individual patient and may be used as a target for monitoring of leukemic burden (MRD, minimal residual disease) during the treatment. In general, MRD is an important prognostic factor, which influences the treatment intensity. Two standardized methods are currently used for its monitoring. The first one is based on the detection of clonal specific Immunoglobulin and/or T-cell receptor genes rearrangements (and thus cannot be used for CML cases) at the DNA level, the second one utilizes detection of the BCR/ABL fusion gene at the mRNA level. Our aim was to optimize and standardize the process to find individual patient breakpoints on Ph chromosome and to use it for MRD quantification. We found the breakpoint in 80 % cases. The MRD data from 15 patients obtained by our method were compared to the levels obtained by standard methods (Ig/TCR and BCR/ABL transcript quantification). In all but 1 patient we found significant discrepancies, raising the questions about leukemic origin and the most accurate method for...
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Elucidating the interactions of interleukin-1alpha with components of the eukaryotic transcription machinery
Zámostná, Blanka ; Pospíšek, Martin (advisor) ; Černý, Jan (referee) ; Mělková, Zora (referee)
4 ABSTRACT Interleukin-1α (IL-1α) is a pleiotropic cytokine and a key mediator of host immune response. It is synthesised as a 31-kDa precursor, that is cleaved by the cysteine protease calpain into the 17-kDa mature IL-1α and the 16-kDa N- terminal peptide of IL-1α (IL-1αNTP). Although IL-1α can be secreted, act on target cells through the surface receptor IL-1RI and trigger the signal transduction pathway, increasing evidence points toward the involvement of IL-1α in certain nuclear processes. IL-1αNTP is highly conserved among higher eukaryotes and contains a nuclear localisation sequence; indeed, both the precursor and IL-1αNTP are found in the cell nucleus. Previously, a genetic interaction of IL-1α with nuclear histone acetyltransferase (HAT) complexes has been reported from mammalian cells and, interestingly, also from the heterologous yeast model. This thesis extends the research of the nuclear function of IL-1α and demonstrates that IL-1α physically associates with the HAT/Core module of yeast SAGA and ADA HAT complexes. Results of the HAT subunit gene knock-out experiments followed by a set of co-immunoprecipitations also suggest a novel model of the yeast SAGA complex assembly, in which ADA appears to represent only a partly functional HAT complex. In its natural milieu of mammalian cells, IL-1α...
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Myeloid lineage involvement in BCR/ABL-positive acute lymphoblastic leukaemia
Hovorková, Lenka ; Zuna, Jan (advisor) ; Mikyšková, Romana (referee)
The Philadelphia chromosome has been discovered in 1960. This chromosomal aberration was mistakenly associated only with chronic myeloid leukaemia (CML) for decade. However, this type of translocation including chromosomes 9 and 22 was found in patients with different type of neoplasia - acute lymphoblastic leukaemia (ALL). Different lineage involvement has been found in these two types of leukaemia. Whereas in Ph-positive ALL, the Philadelphia chromosome is restricted to the lymphoid lineage, in CML patients mostly myeloid cells are those being Ph-positive. Hence it seems quite trivial to distinguish between ALL and CML. But there is a phase of CML called lymphoid blast crisis which is indistinguishable from ALL. The possibility of distinguishing between CML in lymphoid blast crisis and ALL would inhere in determining myeloid lineage involvement. Actually it had been shown that some patients with Ph+ ALL have involved also a myeloid lineage. Different types of treating protocols are used in CML and ALL. In addition, prognoses for both types of leukaemia are different. Thus it is crucial to distinguish between this two disorders and revealing of any difference can impact the treatment outcome of above mentioned malignancies. Detection of minimal residual disease according to involvement of myeloid or CD34+...
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