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

2019; American Association for Cancer Research; Volume: 9; Issue: 6 Linguagem: Inglês

10.1158/2159-8290.cd-18-0873

2159-8290

Damien Roos‐Weil, Camille Decaudin, Marine Armand, Véronique Della-Valle, M’Boyba Diop, Hussein Ghamlouch, Virginie Ropars, Cécile Hérate, Diane Lara, Éric Durot, Rima Haddad, Elena Mylonas, Frédérik Damm, Françoise Pflumio, Bilyana Stoilova, Marlen Metzner, Olivier Elemento, Philippe Dessen, Valérie Camara‐Clayette, François-Loı̈c Cosset, Els Verhoeyen, Véronique Leblond, Vincent Ribrag, Pascale Cornillet‐Lefèbvre, Philippe Rameau, Nabih Azar, Frédéric Charlotte, Pierre Morel, Jean‐Baptiste Charbonnier, Paresh Vyas, Thomas Mercher, Saïd Aoufouchi, Nathalie Droin, Christel Guillouf, Florence Nguyen‐Khac, Olivier Bernard,

PI3K/AKT/mTOR signaling in cancer

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 Waldenström 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.This article is highlighted in the In This Issue feature, p. 681.