Affordable Access

deepdyve-link
Publisher Website

Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia.

Authors
  • Song, Lili1
  • Yu, Bo1
  • Yang, Yi1
  • Liang, Jianwei1
  • Zhang, Yingwen1
  • Ding, Lixia2
  • Wang, Tianyi1
  • Wan, Xinyu1
  • Yang, Xiaomin1
  • Tang, Jingyan3
  • Wang, Shengyue4
  • Li, Benshang1
  • Li, Yanxin5
  • Feng, Haizhong1
  • 1 Shanghai Jiao Tong University, Shanghai, China. , (China)
  • 2 Shanghai Children's Medical Center, Shanghai, China. , (China)
  • 3 shanghai children's medical center, Shanghai, China. , (China)
  • 4 Ruijin Hospitial affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. , (China)
  • 5 Shanghai Children's Medical Center,Shanghai Jiao Tong UniversitySchool of Medicine, Shanghai, China. , (China)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Sep 08, 2020
Identifiers
DOI: 10.1182/blood.2020005622
PMID: 32898863
Source
Medline
Language
English
License
Unknown

Abstract

Leukemogenesis is characterized by chromosomal rearrangements with additional molecular disruptions, yet the cooperative mechanisms are still unclear. Using whole-exome sequencing of a pair of monozygotic twins discordant for childhood acute lymphoblastic leukemia (ALL) with ETV6-RUNX1 (E/R) gene fusion successively after birth, we identified the R209C mutation of G protein subunit alpha o1 (GNAO1) as a new ALL risk loci. Moreover, GNAO1 missense mutations are only recurrent in ALL patients and are associated with E/R fusion. Ectopic expression of the GNAO1 R209C mutant increased its GTPase activity and promoted cell proliferation and cell neoplastic transformation. Combined with the E/R fusion, the GNAO1 R209C mutant promoted leukemogenesis through activating PI3K/Akt/mTOR signaling. Reciprocally, activated mTORC1 phosphorylated p300 acetyltransferase, which acetylated E/R and thereby enhanced the E/R transcriptional activity of GNAO1 R209C. Thus, our study provides clinical evidence for the functional cooperation of GNAO1 mutants and E/R fusion, suggesting GNAO1 as a potential therapeutic target in human leukemia. Copyright © 2020 American Society of Hematology.

Report this publication

Statistics

Seen <100 times