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  • Periodic Reporting for period 2 - HemNichMDS (Functional and Molecular Analyses of the Interplay between Hematopoietic and Mesenchymal Niche Cells in Human Myelodysplastic Syndromes.)

HemNichMDS Report Summary

Project ID: 639795
Funded under: H2020-EU.1.1.

Periodic Reporting for period 2 - HemNichMDS (Functional and Molecular Analyses of the Interplay between Hematopoietic and Mesenchymal Niche Cells in Human Myelodysplastic Syndromes.)

Reporting period: 2017-02-01 to 2018-07-31

Summary of the context and overall objectives of the project

Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell diseases mainly affecting the elderly (45/100,000 in >70 years). The prevalence of MDS is expected to rise mainly as a result of an aging population. MDS is characterized by ineffective production of mature blood cells with peripheral cytopenias and the propensity to evolve to acute myeloid leukemia. Most MDS patients rely on continuous blood transfusions resulting in significant costs to healthcare systems and, most importantly, secondary effects leading to complications and patient deaths. The only potential curative treatment for MDS is hematopoietic stem cells (HSC) transplantation, which is limited to younger patients with suitable donors (<10% of MDS patients).

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the past funding period, the team has been actively working with clinical collaborators to obtain and biobank a large number of bone marrow biopsies from patients with MDS. These samples are instrumental in our screening effort but also constitute an invaluable resource for the functional validation of our findings.
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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Although suspected to be of critical relevance to MDS pathogenesis, little is known about the epigenetic alterations in MDS-associated niche cells (e.g. MSCs, ECs). Likewise the molecular mechanisms by which these alterations are acquired and propagated are largely elusive. Our ongoing research goes beyond state of the art by interrogating these fundamental aspects of MDS biology in primary patient material acquired with well-defined clinical data, and at different disease stages. Analysis of these longitudinal samples will allows us to gain critical insights into the dynamics of niche changes. This should allow us to define disease-features that we could translate into niche-targeted therapies for the future benefit of patients.

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).
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