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Lineage plasticity of leukemic blasts. Importance for detection of minimal residual disease and study of hematopoesis
Vakrmanová, Barbora ; Mejstříková, Ester (advisor) ; Šálek, Cyril (referee) ; Klener, Pavel (referee)
Acute leukemia is the most common malignancy in children. According to the origin of the leukemic blasts, two types of leukemia are distinguished - lymphoid (ALL) and myeloid (AML). The focus of this thesis is lineage plasticity of the leukemic blasts. In about 2-5% of leukemias, blasts share immunophenotypic features of both lymphoid and myeloid lineages. In international retrospective study we showed superior overall survival in patients treated according to lymphoid type of protocol compared to patients treated to myeloid type of protocol, especially in cases with CD19 positivity on the blasts. Another type of the plasticity and diagnostic uncertainty in leukemia is ALL with early switch to monocytic lineage. About 8% of B cell precursor ALL underwent monocytic switch in our consecutive cohort. This phenomenon is more common among DUX4r, PAX5-P80R and ZNF384r leukemias. Discrepancy between minimal residual disease (MRD) measured by flow cytometry and quantitative assessment of immunoreceptor rearrangements method occurs because of the loss of B-lymphoid markers. We investigated transdifferentiation process by mass cytometry. By the multilabel panel we were able to determine the sequence of changes in proteins and transcription factors by new tviblindi algorithm. Targeted treatment, such as...
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Lineage plasticity of leukemic cells
Slámová, Lucie ; Mejstříková, Ester (advisor) ; Brdička, Radim (referee) ; Machová Poláková, Kateřina (referee)
So far, the lymphoid to myeloid lineage switch during the treatment of B cell precursor acute lymphoblastic leukemia (BCP ALL) was identified only rarely in patients with the MLL gene rearrangement. We discovered a novel BCP ALL subset switching to monocytoid lineage during an early phase of the treatment - swALL ("switching" ALL) with no MLL gene rearrangement. The proportion of swALL cases among BCP ALLs was unexpectedly high (3-4%). All swALLs have expressed the CD2 antigen (LFA-2). The upregulation of C/EBPα gene and hypomethylation of the CEBPA promoter were significant in blasts already at diagnosis, proceeding the lineage switch in the majority of the cases. SwALL patients were characterized by unique subpopulation of the cells coexpressing B lymphoid and monocytoid markers. Changes in the gene expression of M-CSFR, GM- CSFR and other genes accompanied the lineage switch. The lineage switch could be recapitulated in vivo and in vitro. Even if the children patient with swALL respond slowly to initial therapy, the prognosis is comparable to "other" BCP ALLs. Risk-based ALL therapy appears to be the treatment of choice for swALL. Powered by TCPDF (www.tcpdf.org)
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Regulation of leukocyte signal transduction by membrane adaptor proteins and kinases
Borna, Šimon ; Brdička, Tomáš (advisor) ; Černý, Jan (referee) ; Mejstříková, Ester (referee)
Signaling pathways must be finely tuned to assign a signal of appropriate strength and duration to the receptor stimulation. Their dysregulation can be very harmful. The consequences of dysregulated signaling pathways vary from autoimmunity, immunodeficiency, and autoinflammation to abnormal proliferation and cancer. In my thesis I aimed to characterize the roles of kinases and membrane associated or transmembrane adaptor proteins in signaling pathways downstream of different receptors. First, I was comparing the roles of SRC family kinases (SFK) in the initiation of antigen receptor signaling in B cells and in T cells. This effort resulted in the manuscript where we re-evaluated current data, which suggested that SYK can initiate BCR signaling independently of SFK. We show that much lower SFK activity is required for the initiation of BCR signaling than for TCR signaling, but we did not find any evidence for SFK-independent signal transduction. We also found that multiple factors are responsible for setting the higher threshold for SFK activity required to initiate signaling by TCR, including differences between SYK and ZAP-70, structure of the antigen receptor itself and separation of the receptor from transmembrane adaptor LAT, which is a major hub coordinating the formation of TCR signalosome....
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Lineage plasticity of leukemic cells
Slámová, Lucie ; Mejstříková, Ester (advisor) ; Brdička, Radim (referee) ; Machová Poláková, Kateřina (referee)
So far, the lymphoid to myeloid lineage switch during the treatment of B cell precursor acute lymphoblastic leukemia (BCP ALL) was identified only rarely in patients with the MLL gene rearrangement. We discovered a novel BCP ALL subset switching to monocytoid lineage during an early phase of the treatment - swALL ("switching" ALL) with no MLL gene rearrangement. The proportion of swALL cases among BCP ALLs was unexpectedly high (3-4%). All swALLs have expressed the CD2 antigen (LFA-2). The upregulation of C/EBPα gene and hypomethylation of the CEBPA promoter were significant in blasts already at diagnosis, proceeding the lineage switch in the majority of the cases. SwALL patients were characterized by unique subpopulation of the cells coexpressing B lymphoid and monocytoid markers. Changes in the gene expression of M-CSFR, GM- CSFR and other genes accompanied the lineage switch. The lineage switch could be recapitulated in vivo and in vitro. Even if the children patient with swALL respond slowly to initial therapy, the prognosis is comparable to "other" BCP ALLs. Risk-based ALL therapy appears to be the treatment of choice for swALL. Powered by TCPDF (www.tcpdf.org)
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