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Rôle de deux suppresseurs de tumeurs TET2 et P53 dans un contexte hématopoïétique

Abstract : Two tumor suppresors, TET2 and P53, play an important role in the homeostasis of hematopoietic stem cells and have been found mutated in hematological malignancies. They are also involved in cell cycle control and DNA repair mechanisms, including the base excision repair pathway (BER). In the first part of this work, we showed that TET2 overexpression and the consequent increase of 5hmC, inhibit cell cycle progression particularly G1/S transition and induces centrosome instability associated with chromosomal instability in Ba/F3 cellular model. In addition, overexpression of TET2 induces increased mutagenesis particularly transitions C->T at CpG sites in a context deficient in thymidine DNA glycosylase (TDG), a protein initiating BER. In the second part of this work, we have shown that p53 activation by MDM2 antagonists has deleterious effect on all haematopoietic progenitors. These antagonists also induce cytotoxicity not only in the early stages of megakaryopoiesis but also mainly in the late stages. This cytotoxicity is not reversible, in contrast to what is observed in clinic, and can not be restored by increasing doses thrombopoietin. To conclude, TET2 and P53 must be strictly controlled to ensure homeostasis and genetic stability of the hematopoietic cells.
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Submitted on : Thursday, September 21, 2017 - 2:32:04 PM
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Emna Mahfoudhi. Rôle de deux suppresseurs de tumeurs TET2 et P53 dans un contexte hématopoïétique. Cancer. Université Paris Saclay (COmUE), 2016. Français. ⟨NNT : 2016SACLS026⟩. ⟨tel-01591482⟩

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