Fiche publication
Date publication
avril 2019
Journal
Cancer discovery
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CORNILLET-LEFEBVRE Pascale
Tous les auteurs :
Roos-Weil D, Decaudin C, Armand M, Della-Valle V, Diop MK, Ghamlouch H, Ropars V, Herate C, Lara D, Durot E, Haddad R, Mylonas E, Damm F, Pflumio F, Stoilova B, Metzner M, Elemento O, Dessen P, Camara-Clayette V, Cosset FL, Verhoeyen E, Leblond V, Ribrag V, Cornillet-Lefebvre P, Rameau P, Azar N, Charlotte F, Morel P, Charbonnier JB, Vyas P, Mercher T, Aoufouchi S, Droin N, Guillouf C, Nguyen-Khac F, Bernard OA
Lien Pubmed
Résumé
The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA binding sequences and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenstrom macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA binding affinity of the protein and allows the mutant protein to bind and activate more frequently promoter regions with respect to wild type protein. Mutant SPI1 binding at promoters activates gene-sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest.
Référence
Cancer Discov. 2019 Apr 24;:
