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ERC

ApoptoMDS Report Summary

Project ID: 638145
Funded under: H2020-EU.1.1.

Periodic Reporting for period 2 - ApoptoMDS (Hematopoietic stem cell Apoptosis in bone marrow failure and MyeloDysplastic Syndromes: Friend or foe?)

Reporting period: 2016-12-01 to 2018-05-31

Summary of the context and overall objectives of the project

Patients with inherited bone marrow failure syndromes such as Dyskeratosis congenita and Fanconi anemia do not only develop hematopoietic failure with anemia, bleeding tendency and susceptibility to infection, but moreover are at risk to develop myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Once the malignancy arise, the prognosis of the patients is very poor and strategies are required to prevent rather than to treat malignant transformation. While hematopoietic cells of affected patients are particularly sensitive to cell death signals, cells resistant to apoptosis (a form of programmed cell death) are selected during the process of malignant transformation.
We are analyzing the cell death mechanisms in inherited bone marrow failure syndromes and secondary MDS/AML in order to understand whether and how apoptosis contributes to bone marrow failure and how it influences leukemogenesis. In addition, we are inhibiting apoptosis in hematopoietic cells with the aim to mitigate the hematological phenotype of affected individuals. We hypothesize that inhibition of bone marrow failure, and as a consequence reduction of compensatory proliferation and selection pressure, leads to delayed malignant transformation. To investigate these topics, we are using mouse models and analyzing patient-derived samples.

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

We successfully generated mouse models for different bone marrow failure syndromes and secondary leukemia.
We observed that apoptosis inhibition changes the phenotype in some of these models significantly.
We included first patient samples in our study.

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)

We aim at identifying the role of apoptosis signaling for pathogenesis of bone marrow failure syndromes and secondary MDS / AML. We hypothesize that keeping premalignant cells alive is able to prevent leukemia, although this is in stark contrast to the well-established “hallmark of cancer” model proposed by Hannahan and Weinberg.
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