Autophagie, une cible thérapeutique potentielle dans les leucémies aiguës myéloïdes exprimant FLT3-ITD

Abstract : Acute myeloid leukemias (AMLs) are a family of hematological malignancies characterized by an accumulation in the marrow and blood of hematopoietic progenitors blocked in their differentiation process. The FLT3-ITD mutation is found in 20-25% of AMLs and is associated with a poor prognosis. Different FLT3 inhibitors have been developed and some of them are clinically tested but resistance to treatment has been observed in many patients. A better understanding of AML biology is necessary in order to improve the treatment of AMLs. My thesis project focused on the analysis of the autophagic process, which is one of the mechanisms described in the resistance of cancer cells. In this study, we found that the FLT3-ITD expression increases basal autophagy in AML cells, and that the receptor inhibition reduced this autophagy in primary patient samples and cell lines. We show that autophagy is required for proliferation and survival in vitro and in vivo of leukemic cells lines and inhibition of autophagy overcomes resistance to FLT3 inhibitors. In addition, we identified the ATF4 protein as a key actor of the autophagy process induced by the FLT3-ITD mutation. These results suggest that targeting autophagy or ATF4 may represent a promising and innovative therapeutic strategy for FLT3 mutated AMLs.
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Quentin Heydt. Autophagie, une cible thérapeutique potentielle dans les leucémies aiguës myéloïdes exprimant FLT3-ITD. Cancer. Université Paul Sabatier - Toulouse III, 2017. Français. ⟨NNT : 2017TOU30366⟩. ⟨tel-02275026⟩

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