A 4-year full-time PhD position is available in our laboratory
to identify druggable mechanisms for an improved treatment of fibrosis in chronic blood cancer.
Primary Myelofibrosis (PMF) is an incurable blood cancer caused by mutations in hematopoietic stem cells. It belongs to a related group of blood cancers known as "BCR-ABL1-negative myeloproliferative neoplasms (MPN)". In PMF the bone marrow tissue is gradually replaced by fibrous scar-like material (myelofibrosis; MF). Over time, this leads to progressive bone marrow failure and failure of the body to produce blood cells. The only potentially curative option is transplantation of healthy donor bone marrow cells (allogeneic hematopoietic stem cell transplantation; allo-HSCT). However, the majority of patients are not eligible for this high-risk procedure due to age and comorbidities.
In our recent work (1-3), we identified the long-sought fibrosis-driving cells of the bone marrow in murine and human bone marrows. We are now in the position to determine the molecular, temporal and spatial "turning point" from a myeloproliferative to a fibrotic bone marrow. In this PhD project, we will generate a high-resolution map of the stepwise fibrotic transformation of the bone marrow by applying cutting edge multiomic and spatial transcriptomics technologies in established murine models and patient samples. It is the central goal to identify mechanisms specific to the progression of fibrosis which will be functionally validated.
The PhD candidate will use state-of-the-art methods including genetic fate tracing, genetic murine models, bone marrow transplantation, confocal imaging and single-cell RNA methodologies with spatial resolution. Biocomputational experience is expected.
- Leimkühler NB, Gleitz HFE, Ronghui L, Snoeren IAM, Fuchs SNR, Nagai JS, et al. Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis. Cell Stem Cell 2021 Apr 1;28(4):637-52.e8.
Available from: http://dx.doi.org/10.1016/j.stem.2020.11.004
- Kramann R, Schneider RK. The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis. Blood. 2018 May 10;131(19):2111-9.
Available from: http://dx.doi.org/10.1182/blood-2018-02-834820
- Schneider RK, Mullally A, Dugourd A, Peisker F, Hoogenboezem R, Van Strien PMH, et al. Gli1 Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target. Cell Stem Cell. 2017 Jun 1;20(6):785-800.e8.
Available from: http://dx.doi.org/10.1016/j.stem.2017.03.008