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Impact of the H3.3K27M Mutation on the Response to Treatments of DIPG Cells
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Edité par CCSD -
International audience. Diffuse Intrinsic Pontine Gliomas (DIPG) are pediatric brain tumors characterized by a dismal prognosis due to, in part, their high chemoresistance. The main molecular alteration in DIPG is the H3.3K27M mutation, disrupting the PRC2 complex activity and leading to a loss of H3K27me3 in cancer cells. Recently, it has been described as one of the main driver mutation in tumorigenesis. Nevertheless, the impact on resistance to treatments remains poorly documented. In this context, the laboratory has established DIPG clones knockout for this mutation to evaluate its full scope. My project aims to assess and decipher the impact of the H3.3K27M mutation on the response to the treatment of DIPG cells.The role of the mutation in response to treatments was evaluated using a panel of a hundred molecules selected based on the literature with Dr. Eddy Pasquier (CRCM, Marseille). Out of these molecules, two cardiac glycosides, inhibitors of Na+/K+ ATPase, have synthetic lethality with the presence of the H3.3K27M mutation in DIPG cells. Interestingly, it also correlates with an alteration, due to the mutation, of calcium signaling molecular signature from a transcriptomic analysis thanks to Dr. Marie Castets (CRCL, Lyon). In addition, we validated that Proscillaridin A induces apoptosis but, above all, that it reduces H3K27ac, a histone mark increase by the H3.3K27M mutation.Ultimately, this project aims to pave the way for innovative drug combinations to improve DIPG treatment.
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