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Anomalies moléculaires dans la macroglobulinémie de Waldenström : identification d’une mutation somatique récurrente dans le gène codant pour le facteur de transcription SPI1/PU.1 et description de ses conséquences fonctionnelles

Abstract : The ETS-domain transcription factors are divided into subfamilies based on protein similarities, DNA binding sequences and interaction with cofactors. They are regulated by extracellular clues and contribute to a variety of cellular processes, including proliferation and transformation. ETS genes are targeted by oncogenic processes through chromosomal translocations and copy number gains. The PU.1/SPI1 gene is also targeted by inactivating point mutations in human myeloid malignancies. We investigated a recurrent somatic missense mutation (Q226E) of the PU.1/SPI1 gene in Waldenström macroglobulinemia, a human B-cell lymphoproliferative disorder. The mutation changes DNA binding of the mutant protein from classical SPI1 to ETS1-like sequences, shifting the balance from binding to promoter regions from enhancers. Increased binding by mutant SPI1 at promoters activates gene expression of intracellular signaling pathways typically promoted by other ETS factor family members. The functional consequences are decreased terminal B-cell differentiation in a model cell line and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration DNA binding specificity leading to differentiation arrest. The demonstration that a somatic point mutation subtly changes the balance of genome binding provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.
Keywords : PU.1 SPI1 NGS Waldenström
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Damien Roos-Weil. Anomalies moléculaires dans la macroglobulinémie de Waldenström : identification d’une mutation somatique récurrente dans le gène codant pour le facteur de transcription SPI1/PU.1 et description de ses conséquences fonctionnelles. Cancer. Université Paris Saclay (COmUE), 2018. Français. ⟨NNT : 2018SACLS517⟩. ⟨tel-02420532⟩

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