Title: Impact of hemato-oncological therapies on genomic stability and differentiation capacity of human bone marrow-derived mesenchymal stromal cells in the context of therapy-related hematopoietic insufficiency and development of secondary myeloid neoplasms
Institute:Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf
Background: Hematotoxicity and development of therapy-related myeloid neoplasms (tMN) are common side effects of antineoplastic therapies like chemotherapy, radiation and small molecules causing relevant morbidity and mortality. Acknowledging the pivotal role of mesenchymal stromal cells (MSC) for the regulation of healthy hematopoiesis, we hypothesize that antineoplastic therapies impair genomic stability and differentiation of MSC thereby contributing to the development of hematopoietic insufficiency and tMN.
Aim: The project aims to comprehensively characterize the effects of antineoplastic therapies on functionality of healthy bone-marrow derived MSC including phenotype, genotype, differentiation and hematopoietic support function. Results from this projects should enable a better understanding of underlying mechanisms and help to develop strategies to ameliorate incidence and severity of hematotoxicity as well as the risk of tMN.
Experimental procedure / working programme: For this purpose, in a first step healthy MSC will be exposed in a vitro cell-culture system to chemotherapy, ionizing irradiation and small molecules. Afterwards, they will be investigated regarding their growth and differentiation potential, senescence, apoptosis, cell cycle, behavior and hematopoietic support using established assays and gene expression profiling will be performed using RNA sequencing. In a second step the identified candidate molecules or pathways (identified in step 1) will be evaluated with regard to their pathophysiological relevance in "gain and loss of function experiments" employing vector-, siRNA and CRISPR/Cas-based methods. In a third step the impact of therapy-induced genomic instability for the development of tMN will be investigated. Here, basal expression of susceptibility factors (DNA repair genes, DNA damage response) will be measured in healthy MSC and correlated with the expression found in MSC derived from patients with tMN. Furthermore, the gene expression profile of healthy MSC after exposure to cytotoxic agents (step 1) will be compared with the gene expression profile of patient-derived MSC followed by functional validation of identified candidate molecules.
The ideal candidate has a strong background in toxicology/pharmacology, cell culture systems, gene expression profiling, molecular cell biology and/or stem cell biology. High motivation and commitment to the project´s subject is expected.
Interested candidates are welcome to apply for this project. Please note to fill in the project number 3a in the application form.
Recommended literature for further information
- Geyh S et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia. 2013 Sep;27(9):1841-51. doi: 10.1038/leu.2013.193. Epub 2013 Mar 29
- Geyh S et al. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia. 2016 Mar;30(3):683-91. doi: 10.1038/leu.2015.325. Epub 2015 Nov 25.
- Schroeder T Mesenchymal stromal cells in myeloid malignancies. Blood Res. 2016 Dec;51(4):225-232. doi: 10.5045/br.2016.51.4.225. Epub 2016 Dec 23.
- Geyh S et al. Transforming growth factor β1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2018 Sep;103(9):1462-1471. doi: 10.3324/haematol.2017.186734. Epub 2018 May 17.
- Baberg F et al. Secretome analysis of human bone marrow derived mesenchymal stromal cells. Biochim Biophys Acta Proteins Proteom. 2019 Apr;1867(4):434-441. doi: 10.1016/j.bbapap.2019.01.013.