National Repository of Grey Literature 5 records found  Search took 0.00 seconds. 
Regulatory mechanisms in normal and malignant granulopoiesis
Kardošová, Miroslava ; Alberich-Jorda, Meritxell (advisor) ; Stopka, Tomáš (referee) ; Balounová, Jana (referee)
Neutrophils, known primarily as key players in defense against invading pathogens, represent an essential component of both the innate and adaptive immunity. Continuous production of large quantities of neutrophils is ensured by a complex process termed granulopoiesis. In order to maintain a stable neutrophilic population, granulopoiesis requires to be tightly regulated. Moreover, impaired granulopoiesis may lead to aberrant bone marrow function and, ultimately, give rise to acute myeloid leukemia (AML). Despite decades of research, the mechanisms regulating granulopoiesis are still unclear. In particular, the CCAAT/enhancer binding protein (C/EBP) family of transcription factors plays a critical role in this process. C/EBPα acts as a master regulator of granulopoiesis mainly by orchestrating expression of its target genes, which will mediate granulocytic differentiation. Thus, characterization of novel C/EBPα target genes is critical for a better understanding of the molecular mechanisms that regulate granulopoiesis. Previously, we showed that another C/EBP member, CEBPG, is a direct target of C/EBPα. In the first part of the present work, we addressed the unknown role of C/EBPγ in granulopoiesis. We observed that Cebpg conditional knockout (KO) mice, which have the Cebpg gene ablated specifically...
Molecular basis of clonal heterogeneity of hematological diseases
Babošová, Oľga ; Láníková, Lucie (advisor) ; Alberich-Jorda, Meritxell (referee) ; Horváthová, Monika (referee)
Tumor heterogeneity has been recognized for decades. The molecular mechanisms impacting clonal heterogeneity in hematological diseases, specifically myeloproliferative neoplasms (MPN) and mantle cell lymphoma, with the focus on several inherited genetic factors, inflammation, the protective mechanisms of DNA damage response (DDR) in the leukemic transformation and the treatment strategies are the focus of this thesis. Firstly, I focus on studying germline JAK2 variants and how these may influence the initiation and progression of MPN diseases, and even contribute to further genomic alterations in the mutated clone. A study performed by our cooperating lab in Utah, USA,1 analyzing the mutational landscape of 31 JAK2 V617F-positive polycythemia vera (PV) patients identified two novel germline mutations in JAK2 gene, JAK2 T108A and JAK2 L393V. Another study2 , performed by our cooperating lab in Olomouc, Czech Republic, characterized two germline JAK2 mutations, E846D and R1063H, in a case of hereditary erythrocytosis accompanied by megakaryocytic atypia. The JAK2 R1063H variant was initially described in 3 out of 93 PV patients that were JAK2 V617F-positive.3 Our aim was to identify the role of selected inherited mutations in JAK2 gene in the initiation and progression of myeloproliferative...
The transcription factor C/EBPƴ as a novel regulator in mast cell development and function
Jedlička, Marek ; Alberich-Jorda, Meritxell (advisor) ; Černý, Jan (referee)
Mast cells contribute to the activities of innate and adaptive branches of the immune system. They participate in pro-inflammatory responses to a wide range of pathogens, such as parasites, bacteria, and other foreign agents. These beneficial properties are in contrast to the contribution of mast cells to certain pathologies, such as asthma, allergy, autoimmune disorders, anaphylaxis, and systemic mastocytosis. Thorough knowledge of mast cell biology in health and disease is critical for the development of new therapeutic approaches. However, molecular mechanisms that control mast cell development and function are still incompletely defined. Our preliminary data indicate that the transcription factor C/EBP is a key player in mast cell biology. Here, using in vitro and in vivo models, we determine how C/EBP regulates the commitment of hematopoietic progenitors towards mast cells, and modulates mast cells function. These efforts provide novel insights to the role of C/EBP in hematopoiesis, and contribute to a better understanding of the mechanisms governing mast cell biology. Key words Mast cells, C/EBP, transcription factors, bone marrow-derived mast cell cultures, mast cell development, Cebpg conditional knockout mice
Characterization of hematopoietic cells in patients with mature B-cell malignancies
Maswabi, Bokang Calvin ; Živný, Jan (advisor) ; Otáhal, Pavel (referee) ; Alberich-Jorda, Meritxell (referee)
(English) Using flow cytometry we analyzed absolute and relative proportions of hematopoietic stem and progenitors cells (HSPC) populations including hematopoietic stem cells (HSC), multipotent progenitors (MPP), multilymphoid progenitors (MLP) and pro B cells from bone marrow of patients with mature B cell malignancies and in healthy controls. We found lower absolute and relative numbers of MLP and higher relative numbers of HSC were observed in patients when compared to age-matched controls irrespective of bone marrow (BM) involvement. On the other hand significantly decreased absolute numbers of MPP were observed only in patients who had their BM infiltrated by disease. We also confirmed published data showing increasing absolute and relative percentages of MLP with increasing age, decreasing relative percentages of HSC with increasing age, and decreasing absolute and relative pro B cell frequencies with increasing age in healthy subjects. While decreased absolute and relative pro B cell numbers were also found in patient samples as age increased, no significant correlations were detected in patients HSC, MPP or MLP populations. Age-related sub-analysis of PTs samples demonstrated that most of the disease associated changes in HSPC frequencies were observable more prominently in the elderly (>45...
Identification and functional characterization of C/EBPalpha targets in normal and malignant hematopoiesis
Zjablovskaja, Polina ; Alberich-Jorda, Meritxell (advisor) ; Stopka, Tomáš (referee) ; Fuchs, Ota (referee)
Thehematopoieticsystemisahighlyorganizedstructure, whichhastobetightly regulatedinordertofunctionproperly.Abnormalitiesinhematopoieticdevelopmentmaylead tohematologicaldisorders,suchasacutemyeloidleukemia(AML).Thefunctionalityofthe hematopoieticsystemlargelyreliesontranscriptionfactors.C/EBPtranscriptionfactoris knownasoneofthe majorhematopoieticregulators,requiredforthefunctionalityof hematopoieticstemcellsaswellasformyeloidlineagedevelopment.Importantly,C/EBP expressionisalteredinalargeproportionofAMLcases.C/EBPregulateshematopoiesis mainlythroughorchestratingexpressionofitstargetgenes.ManyoftheC/EBPtargetshave previouslybeenshowntoplayaroleinthehematopoieticsystemandtobeinvolvedin leukemictransformation. That makesidentificationofnovel C/EBP targetsandtheir functionalcharacterizationanexcitingsubjectofresearch.Hereweidentifiedalistofgenes whoseexpressiondependsontheactivityofC/EBPthesocalledC/EBPsignature. We demonstratedthattreatment withhistonedeacetylase(HDAC)inhibitorsreactivatesthe expressionofthesegenesincellswithnon-functionalC/EBP.Inaddition,wedemonstrated thattreatmentwiththeHDACinhibitorspromotesmyeloiddifferentiationinAMLsamples carryingbi-allelicCEBPA mutationsandcharacterizedbythereducedexpressionofthe...

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