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The Role of T-cell Receptor in Lymphoma
Kulinich, Viktoriia ; Havránek, Ondřej (advisor) ; Alberich Jorda, Meritxell (referee)
T lymphomas are malignant tumors that could arise from the T cell of any type and developmental stage. Their clinical presentation could largely vary from indolent to very aggressive form. Its exact pathophysiology is still not completely understood; therefore, it is critical to uncover the main mechanism underlying T-lymphoma development and growth to guide rational treatment. T- cell receptor (TCR) is a critical sensor and major determinant of T-cell fate. Therefore, we aimed to assess the function of TCR in T-cell lymphomas. We hypothesized that TCR might provide tumor cells with proliferative signals even in the absence of antigen stimulation. Using model human T-cell lymphoma derived cell lines expressing TCR, we investigated consequences following the knockout (KO) of TCR and CD3. We showed that TCR KO was associated with decreased cellular growth and related changes in cell cycle, however other proliferative functions seem to be uncompromised. TCR KO was also associated with a decrease of AKT kinase activity. Our RNA sequencing-based comparison of unmodified and TCR KO cells uncovered alterations in several signaling pathways important for cell survival. Among the altered were WNT, NF-κB, Jak/STAT and others. Additionally, TCR loss was associated with defects in antigen presentation....
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Tumor Specific Signaling in T-Cell Lymphoma
Kulinich, Viktoriia ; Havránek, Ondřej (advisor) ; Kužílková, Daniela (referee)
T lymphomas are malignant tumors arising from T cells; they represent a rare variant of non-Hodgkin's lymphomas. As in other cancers, tumor T cells need to modify their signaling to support their growth and survival. T-lymphoma tumor cells are capable to adapt various signaling cascades important also in normal healthy T cells to their benefit. The aim of this work is to summarize tumor-specific signaling typical for different types of T-cell lymphomas; both, identical to the signaling of normal T lymphocytes and altered by tumor specific somatic mutations. Detailed focus is on T lymphoma most frequent and important alterations and signaling pathways. These are specifically alterations of signaling pathways associated with T-cell receptor, JAK/STAT cytokine signaling, and Notch signaling. These pathways are particularly important for the differentiation and growth of T lymphocytes in general, therefore, it is not surprising that these pathways are also often pathologically activated or deactivated in tumor cells. Keywords: lymphocytes, non-Hodgkin lymphomas, T-cell receptor, leukemia, JAK/STAT signaling, Notch signaling, oncogenic signaling pathways
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The Role of B-cell Receptor Signaling in Lymphoid Malignancies
Kochmannová, Kateřina ; Havránek, Ondřej (advisor) ; Štěpánek, Ondřej (referee)
The aim of this thesis is to review current knowledge about tumor-specific B cell receptor (BCR) signaling and related novel therapy options in B-cell malignancies with the main focus on non-Hodgkin lymphomas (NHL). To a certain degree, the pathogenic BCR signaling mirrors normal forms of BCR signaling, antigen-induced and tonic. Differences between antigen- dependent and antigen-independent forms of BCR signaling are well characterized in two major subtypes of diffuse large B-cell lymphoma, the most common type of NHL. In addition to the conventional chemotherapy, several BCR inhibitors targeting BTK and PI3K have been approved for the treatment of lymphoid malignancies. However, improvements in the tumor specificity, toxicity profiles and patients selection are needed. A better understanding of BCR signaling deregulation and overall tumor pathogenesis is believed to further improve NHL treatment outcomes. Keywords: B-cell malignancies, non-Hodgkin lymphoma, B-cell receptor, tumor signaling, targeted therapy, inhibitors
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