Periodic Reporting for period 3 - HemNichMDS (Functional and Molecular Analyses of the Interplay between Hematopoietic and Mesenchymal Niche Cells in Human Myelodysplastic Syndromes.)
Reporting period: 2018-08-01 to 2020-01-31
Increasing evidence indicates that myeloid neoplasms can be triggered by abnormal functional properties of the bone marrow microenvironment in mice. However, it remains to be seen whether this also applies to human hematopoietic neoplasms. Our work revealed that patient-derived mesenchymal niche cells are essential to propagate human MDS HSCs in vivo, thus highlighting the crucial role of the niche in human MDS. Moreover, our data indicate that human MDS hematopoietic cells may “educate” their niche environment into a self-reinforcing one.
The goal of our proposal is to decipher the interplay between hematopoietic and mesenchymal niche cells in human MDS, and to assess innovative means by which we could target diseased cells to improve MDS patient outcomes.
We will perform a comprehensive molecular characterization of highly purified primary mesenchymal niche cells to define new prognostic and/or therapeutic niche factors in MDS.
More importantly, we will take advantage of our unique xenograft model of MDS to translate our findings into groundbreaking novel therapeutic strategies for MDS patients, by disrupting essential niche/MDS stem cell interactions.
Molecular characterisation of MSCs has been initiated, and a preliminary data set obtained. Further optimisation of experimental protocols is ongoing.
Preliminary data however, already highlighted a number of epigenetic differences (differentially methylated regions) between healthy and MDS-associated MSCs.
Our team is currently following up on several candidate targets using several model systems (syngeneic mouse models of MDS, patient derived xenograft models (PDX), fully humanised 3D niche models) and experimental approaches, including pharmacological inhibitors developed by collaborating industrial partners.
In addition, we strive to improve current disease modelling strategies. In the past funding period our group established a new workflow that allows for the fast and cost-effective generation of genetically modified NSG mice, which are invaluable to interrogate the role of niche-produced factors in PDX models, in hematological malignancies as well as any other human cancer entities (Tirado-Gonzalez and Czlonka, 2018, Leukemia).
From an ethical perspective, we make every effort to reduce the need for animal experimentation. Therefore, our team has been actively developing a novel, fully humanised, 3D niche model system in which we could experimentally dissect some aspects regarding the cellular interactions between malignant MDS cells and the bone marrow microenvironment (Manuscript in preparation).