A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies-Reference-Cited by-同舟云学术

A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies

Published:2019-08-09 Issue:6453 Volume:365 Page:599-604
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Boettcher Steffen¹²³^ORCID,Miller Peter G.¹²³^ORCID,Sharma Rohan²³^ORCID,McConkey Marie²³^ORCID,Leventhal Matthew²³^ORCID,Krivtsov Andrei V.⁴^ORCID,Giacomelli Andrew O.¹²⁵^ORCID,Wong Waihay²³^ORCID,Kim Jesi³^ORCID,Chao Sherry²⁶^ORCID,Kurppa Kari J.¹⁷,Yang Xiaoping²^ORCID,Milenkowic Kirsten²^ORCID,Piccioni Federica²^ORCID,Root David E.²^ORCID,Rücker Frank G.⁸,Flamand Yael⁹,Neuberg Donna⁹^ORCID,Lindsley R. Coleman¹²,Jänne Pasi A.¹⁷,Hahn William C.¹²^ORCID,Jacks Tyler¹⁰¹¹¹²^ORCID,Döhner Hartmut⁸,Armstrong Scott A.⁴^ORCID,Ebert Benjamin L.¹²³¹³^ORCID

Affiliation:

1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

2. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

3. Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

5. The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.

6. Department of Biomedical Informatics, Harvard University, Boston, MA 02115, USA.

7. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

8. Department of Internal Medicine III, University of Ulm, 89081 Ulm, Germany.

9. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

10. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

11. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

12. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

13. Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Abstract

p53—still hazy after all these years? The gene encoding the p53 tumor suppressor protein is the most frequently mutated gene in human cancer. Yet decades after the gene's discovery, the biology of cancer-associated missense mutations in p53 is still being debated. Previous studies have suggested that missense mutations confer tumor-promoting functions to p53. Boettcher et al. conducted a detailed analysis of p53 missense mutations in human leukemia, drawing on methodologies including genome editing, a p53 saturation mutagenesis screen, mouse models, and clinical data (see the Perspective by Lane). They found no evidence that p53 missense mutations confer an oncogenic gain of function. Rather, the mutations exerted a dominant-negative effect that reduced the tumor suppressor activity of wild-type p53. Science , this issue p. 599 ; see also p. 539

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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