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Origine embryonnaire des manifestations hématologiques de l'Anémie de Fanconi

Abstract : Fanconi anemia (FA), a genetic disorder due to mutations in one of the FANC complementation group genes involved in DNA repair, causes bone marrow failure very early during childhood. We hypothesized that the FA hematopoietic defect could begin in utero, and asked whether during embryonic development, Fanc genes defect could impair the expansion of HSC pool in response to replicative stress, from the first stages of HSCs amplification, focusing on early development times, when HSC amplification takes place both in FL and PL, i.e. E11.5 - E12.5. Our results not only reveals that a deep HSCs defect is already present very early during Fancg-/- mouse development, but also shows for the first time that this is also the case in human FA development. This HSC defect is even more important in the mouse Pl, where high naïve HSC amplification takes place. Actually, this HC/HSC defect is even more important at E12.5 than that described for Fancg-/- adult mice, and resemble more to the BM failure observed in humans. Transcriptomic analysis of HSCs sorted from Fancg-/- E12.5 FL and Pl and from the human FL showed striking highly conserved biological processes involving G protein-coupled receptors pathways, and epigenetic dysregulations, which might represent a hallmark of FA HSCs dysfunction during development. Further studies to explore these epigenetic alterations during fetal life might lead to development of new therapeutic approaches to prevent development of leukemias and cancers in FA patients.
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Carine Halfon-Domenech. Origine embryonnaire des manifestations hématologiques de l'Anémie de Fanconi. Biologie du développement. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066735⟩. ⟨tel-02999201⟩

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