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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
- Source :
- Cancer Discovery, Cancer Discovery, American Association for Cancer Research, 2019, 9 (6), pp.796--811. ⟨10.1158/2159-8290.CD-18-0873⟩, Cancer Discovery, 2019, 9 (6), pp.796--811. ⟨10.1158/2159-8290.CD-18-0873⟩
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
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
- Subjects :
- 0301 basic medicine
[SDV]Life Sciences [q-bio]
Mutation, Missense
lymphoma
Biology
Cell Line
Mice
03 medical and health sciences
0302 clinical medicine
Germline mutation
Mutant protein
Proto-Oncogene Proteins
spi-1/pu.1
pu.1
Animals
Humans
somatic mutation
Nucleotide Motifs
Lenalidomide
Transcription factor
mouse
Cell Proliferation
cll
B-Lymphocytes
Binding Sites
SPI1
Base Sequence
Proto-Oncogene Proteins c-ets
Point mutation
ETS transcription factor family
Promoter
Azepines
Triazoles
Cell biology
cell differentiation
030104 developmental biology
Gene Expression Regulation
Oncology
030220 oncology & carcinogenesis
Myeloid Differentiation Factor 88
Trans-Activators
acute myeloid-leukemia
Waldenstrom Macroglobulinemia
Transcription Factor Gene
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 21598290 and 21598274
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Cancer Discovery
- Accession number :
- edsair.doi.dedup.....bf9becc8f6995ac3fafaabe9c1fc9160