A Recurrent Activating Missense Mutation in Waldenstrom Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cancer Discovery Année : 2019

A Recurrent Activating Missense Mutation in Waldenstrom Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation

Damien Roos-Weil
Rima Haddad
  • Fonction : Auteur
Marlen Metzner
  • Fonction : Auteur
Nabih Azars
  • Fonction : Auteur
Frederic Charlottes
  • Fonction : Auteur
Pierre More
  • Fonction : Auteur

Résumé

The ETS-domain transcription factors divide into subfamilies based on protein sim- ilarities, 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 more frequently bind and activate 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. SIGNIFICANCE: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.

Dates et versions

hal-02173764 , version 1 (04-07-2019)

Identifiants

Citer

Damien Roos-Weil, Camille Decaudin, Marine Armand, Veronique Della-Valle, Mboyba K. Diop, et al.. A Recurrent Activating Missense Mutation in Waldenstrom Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation. Cancer Discovery, 2019, 9 (6), pp.796--811. ⟨10.1158/2159-8290.CD-18-0873⟩. ⟨hal-02173764⟩
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