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Master Thesis

La méthylation de l’ADN dans les leucémies aiguës myéloblastiques : impact de la chélation du fer et valeurs cliniques

Abstract : The identification of genetic abnormalities in acute myeloid leukemia (AML) is now essential to characterize the pathology. These mutations often appear in the regulation genes involved in DNA methylation, in particular DNMT3A, TET2, IDH1 or 2. The objectives of this work were, on the one hand, to study the levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5-hmC) in AML, on the other hand to evaluate the links between methylation of DNA and iron. We measured the levels of 5mC and 5hmC, initially in medullary samples of 25 patients with AML and, secondly, in leukemic lines KG1, HL60, K562, OCI-AML3 and HEL deprived of iron by chelation with the deferoxamine and then re-supplemented with transferrin. The measurements of 5mC and 5hmC were carried out by tandem mass spectrometry using an isotopic internal standard. We show that the levels of 5hmC are different according to the type of AML without apparent variation of the 5mC levels. The 5hmC levels are lower during DNMT3A, IDH 1/2 mutation, or when there is no cytogenetic abnormality and seem weaker during mutation of TET2. When the prognosis of the patients are unfavorable, the rates of 5hmC seem increased. As for the cell lines, the rates of 5mC and 5hmC in the basal state are different according to the studied line and during an iron deprivation, the rates of 5mC increase without variation of the rates of 5hmC. The study and the characterization of the epigenetic signatures of the AML could eventually allow the use of these biomarkers in clinical practice for the personalized management of AML.
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Master Thesis
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Submitted on : Tuesday, October 1, 2019 - 11:12:58 AM
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Simon Chevalier. La méthylation de l’ADN dans les leucémies aiguës myéloblastiques : impact de la chélation du fer et valeurs cliniques. Sciences pharmaceutiques. 2019. ⟨dumas-02302188⟩



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