PROJECT
SUPERVISORS

Project Supervisor

Hélène Gleitz

Background

I started my scientific career studying tissue engineering and regenerative medicine at the University of Manchester (UK), where I focused on stem cell behaviour and hematopoietic development. I obtained my PhD in the group of Brian Bigger where I developed and patented a novel brain-targeted stem cell gene therapy approach, where bone marrow stem cells are corrected using a lentiviral vector and transplanted back into the patient (or mouse) to deliver therapeutic proteins into the brain. This therapy is being brought to a phase I/II clinical trial at the University of Manchester Children’s Hopsital, in partnership with Avrobio.

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In 2018, I started my Marie-Curie LEaDing fellowship in the group of Rebekka Schneider at Erasmus MC, where I specifically focused on the interaction between megakaryocytes and stromal cells and role of inflammation in driving bone marrow fibrosis. I identified that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis and that its absence in bone marrow ameliorates fibrosis, reduces stromal cell activation and decreases inflammation (Gleitz et al. Blood 2020), highlighting its importance as an therapeutic target. Using single-cell genomics, I also generated a comprehensive map of the stroma in myeloproliferative neoplasms in murine models and human samples, and showed that the use of the S100A9-inhibitor Tasquinimod significantly ameliorates the MPN phenotype and fibrosis (Leimkühler, Gleitz et al. Cell Stem Cell 2020).

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Research

Our primary focus is disease-oriented laboratory investigation of clonal myeloid neoplasms, employing a range of genomic technologies as well as classical cellular and molecular biology experimental approaches.

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We are particularly interested in dissecting the interaction between hematopoietic cells and the bone marrow niche, in both steady state and myeloid neoplasms. We focus on the role of genetic haploinsufficiency in hematopoietic stem cell biology and targeted therapy of del(5q) myelodysplastic syndrome (Schneider et al. Cancer Cell 2014Schneider et al. Nature Medicine 2016Ribezzo et al. Leukemia 2019).

One major achievement of our lab has been the identification of fibrosis-driving cells in primary myelofibrosis (PMF). PMF is an incurable blood cancer that leads to the continuous replacement of blood forming cells in the bone marrow by scar tissue, ultimately leading to failure of the body to produce blood cells and to death (Schneider et al. Cell Stem Cell 2017).

Our recent key finding of Gli1+ cells as fibrosis-driving cells allowed us to dissect the molecular and cellular mechanisms of the fibrotic transformation, specifically highlighting the role of inflammation and the use of the S100A9-inhibitor Tasquinimod (Gleitz et al. Blood 2020Leimkühler, Gleitz et al. Cell Stem Cell 2020). We were able to show that mesenchymal stromal cells are functionally reprogrammed in a stage-dependent manner during fibrosis development; MSCs lose their progenitor status in pre-fibrosis and acquire a pro-fibrotic and inflammatory phenotype in the fibrotic stage. We further aim to understand early forms of BM fibrosis for improved diagnostics in patients, all with the ultimate aim to identify novel therapeutic targets to directly block the cellular and molecular changes occurring in BM fibrosis.

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Publications

Gleitz HFE et al. Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN. Blood. 2020

Leimkühler NB, Gleitz HFE, et al. Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis. Cell Stem Cell. 2020