Myelodysplastic Syndromes or Acute Myeloid Leukemia With Multilineage Dysplasia Clinical Trial
Official title:
Characterization of the Mechanisms of Action of Resistance to Azacitidine in High-risk Myelodysplastic Syndromes and Acute Myeloid Leukemia With Multilineage Dysplasia
Myelodysplastic syndromes (MDS) are frequent diseases in elderly patients (median age: 71
years). IPSS classification defines low risk (Low and Intermediate 1), and high risk
(Intermediate 2 and High) MDS. High-risk MDS (MDS-HR) have a high risk of transformation into
acute leukemia with multilineage dysplasia (AML-DML). The success of Azacitidine has been
mainly achieved through a rigorous empirical and clinical research, but the molecular
mechanisms by which this molecule exerts its effects remain poorly characterized. The primary
mode of action of Azacytidine is through DNA demethylation, and integration in to mRNA that
favor traduction inhibition. The impact of this molecule on various cell death programs
involved in the elimination of leukemic cells : apoptosis and autophagy is currently poorly
known.
The research program and clinical studies we proposed focus on two major aspects:
- Main objective: Molecular mechanism of action and resistance to Azacitidine: Role of
apoptosis versus autophagy.
- Secondary Objective: Reversion of Azacytidine resistance using different drugs targeting
apoptosis and/or autophagy. Our laboratory has identified new molecules to selectively induce
different types of cell death (apoptosis or autophagy).
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