Přehled
Supervisor
Lucie Láníková
Project description
Hematopoiesis is a highly organized and dynamic process of blood cell production, progressing hierarchically from hematopoietic stem cells (HSCs) through multipotent progenitors to fully differentiated cells of the myeloid and lymphoid lineages. This system is controlled by a complex network of cytokines and growth factors, with signal transduction predominantly mediated by the JAK-STAT pathway, which regulates proliferation, differentiation, survival, and the stability and trafficking of cytokine receptors.
Long-term HSC function critically depends on the maintenance of genomic integrity, safeguarded by DNA damage response (DDR) mechanisms. DDR orchestrates the detection and repair of DNA lesions, activation of cell-cycle checkpoints, and the repair of both double-strand (DSBs) and single-strand DNA breaks. Additionally, DDR protects stem cells from apoptosis, senescence, and premature functional decline. Impairment or failure of DDR—driven by congenital or acquired genetic variation or chronic cellular stress—leads to the accumulation of DNA damage, HSC exhaustion, disrupted differentiation programs, and activation of stress-induced and inflammatory signaling pathways. These alterations promote the clonal expansion of selectively advantaged hematopoietic cells, support clonal evolution, and may contribute to malignant transformation.
The dissertation focuses on understanding the molecular and genetic mechanisms that disrupt normal blood cell formation. Special attention is given to how inherited predisposition, acquired somatic mutations, and defects in DNA damage response influence stem cell behavior and clonal development. To study these processes, advanced experimental models will be used, including genetically modified animals, iPSC-derived hematopoietic cells, 3D organoids, and in vitro HSC culture systems. The aim of the project is to build a general model that explains how increased signaling activity together with impaired DNA repair control can change blood cell differentiation, clonal dynamics, and support the onset of the malignant myeloid transformation.
Candidate profile
The candidate holds a Master’s degree (or similar) in molecular biology, cell biology or a related life-science field and has a strong interest in hematopoiesis, genome integrity, and molecular mechanisms of disease. Practical experience with standard molecular biology and cell biology techniques is expected. Experience with Western blot analysis is considered an advantage. Bioinformatics skills, including basic data processing, statistical analysis, or work with high-throughput or sequencing data, are highly welcome and will be beneficial for the project. The candidate should be willing to work with murine models. The candidate should be able to work independently as well as part of a research team, demonstrate critical thinking, and show willingness to learn new experimental and computational approaches. Good communication skills in English, reliability, and a proactive attitude toward research are essential.
Suggested reading
Zimolova V, Burocziova M, Berkova L, Grusanovic S, Gursky J, Janotka L, Kasparek P, Pecinova A, Kundrat D, Hrckulak D, Onhajzer J, Jeziskova I, Nekvindova L, Weinbergerova B, Pospisilova S, Doubek M, Alberich-Jorda M, Korinek V, Divoky V, Lanikova L: Germline Jak2-R1063H mutation interferes with normal hematopoietic development and increases risk of thrombosis and leukemic transformation. Leukemia 2025 39(11):2745-2757.
Burocziova M, Danek P, Oravetzova A, Chalupova Z, Alberich-Jorda M, Macurek L: Ppm1d truncating mutations promote the development of genotoxic stress-induced AML. Leukemia 2023 37(11):2209-2220.
Stetka J, Vyhlidalova P, Lanikova L, Koralkova P, Gursky J, Hlusi A, Flodr P, Hubackova S, Bartek J, Hodny Z, Divoky V: Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation. Oncogene 2019 38(28): 5627-5642.
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