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

Cancer Discov. 2019 Jun;9(6):796-811. doi: 10.1158/2159-8290.CD-18-0873. Epub 2019 Apr 24.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Cell Proliferation
  • Gene Expression Regulation*
  • Humans
  • Lenalidomide / pharmacology
  • Mice
  • Mutation, Missense*
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Nucleotide Motifs
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ets / genetics*
  • Proto-Oncogene Proteins c-ets / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Triazoles / pharmacology
  • Waldenstrom Macroglobulinemia / diagnosis
  • Waldenstrom Macroglobulinemia / genetics*
  • Waldenstrom Macroglobulinemia / metabolism*

Substances

  • (+)-JQ1 compound
  • Azepines
  • Myeloid Differentiation Factor 88
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Trans-Activators
  • Transcription Factors
  • Triazoles
  • proto-oncogene protein Spi-1
  • Lenalidomide