Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Zöscher, F.
Analyzing TP53 aberration mediated cytarabine resistance in isogenic AML cell lines and the contribution of mesenchymal stromal cells to resistance using in vitro co culture.
[ Diplomarbeit/Master Thesis (UNI) ] Universität Graz; 2024. pp.103.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Dutta Sayantanee
- Sill Heinz
- Altmetrics:
- Abstract:
- Acute myeloid leukemia (AML) refers to an aggressive variant of leukemia in which mutations in the hematopoietic stem cells (HSCs) of the bone marrow lead to disruption of the entire hematopoietic system. The tumor suppressor TP53 plays an important role in preventing tumor development. Mutations of the TP53 gene are very common in human cancers and are found in up to 50% of cases. In AML patients, TP53 mutations are less common and affect up to 10% of patients but are often associated with very poor prognosis in terms of long-term survival, lower cure rate and increased mortality. In addition, there is an association between TP53 mutations and an increased incidence of resistance to chemotherapeutic agents. Because chemotherapeutic agents cause cell damage, TP53 in its wild-type form stops the cell cycle and induces DNA repair mechanisms or, if it accumulates too much, controlled cell death (apoptosis). However, if TP53 is damaged, it may not be able to perform its functions properly and AML cells will not undergo apoptosis, leading to resistance to chemotherapeutic agents. Furthermore, bone marrow cells can increase the chemotherapy resistance of AML cells. Mesenchymal stromal cells (MSCs) are an important component of the bone marrow and form adipocytes, myocytes, chondroblasts, and osteoblasts. Through inflammatory processes, these MSCs can be altered in their gene expression so that they lose their actual tumor suppressive properties and can even contribute to and enhance the chemotherapy resistance of, for example, AML cells. We created a 2D co-culture cell model with isogenic AML cells, which harbor hotspot TP53 mutations in different allelic states (mono- and bi-allelic), with human MSC cell lines HS-5 and HS-27A to investigate the contribution of the two MSC cell lines to the chemotherapeutic resistance of AML cell lines. In addition, we investigated the effect of different TP53 mutations in different allelic states on chemotherapy resistance during long-term treatment with cytarabine. TP53 mutations were found to have a significant effect on chemotherapeutic resistance, and co-culturing AML and MSC cells significantly increased chemotherapeutic resistance.