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).

Population

Patients with myelodysplastic syndromes or acute myeloid leukemia with multilineage dysplasia treated with Azacitidine

Brief Title

Characterization of the Mechanisms of Resistance to Azacitidine

Official Title

Characterization of the Mechanisms of Action of Resistance to Azacitidine in High-risk Myelodysplastic Syndromes and Acute Myeloid Leukemia With Multilineage Dysplasia

Brief Summary

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

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.