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

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 who were 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 α o1 (GNAO1) as a new ALL risk loci. Moreover, GNAO1 missense mutations are 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 mutation 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 of the functional cooperation of GNAO1 mutations and E/R fusion, suggesting GNAO1 as a therapeutic target in human leukemia.

• Authors: Lili Song, Bo Yu, Yi Yang, Jianwei Liang, Yingwen Zhang, Lixia Ding, Tianyi Wang, Xinyu Wan, Xiaomin Yang, Jingyan Tang, Shengyue Wang, Benshang Li, Yanxin Li, Haizhong Feng
• Journal: Blood (Blood) Vol. 137 Issue 9 Pg. 1181-1191 (03 04 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 32898863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• GNAO1 protein, human
• Oncogene Proteins, Fusion
• TEL-AML1 fusion protein
• GTP-Binding Protein alpha Subunits, Gi-Go

Topics

• Animals
• Carcinogenesis (genetics)
• Cell Line, Tumor
• Core Binding Factor Alpha 2 Subunit (genetics)
• Female
• GTP-Binding Protein alpha Subunits, Gi-Go (genetics)
• HEK293 Cells
• Humans
• Male
• Mice
• Models, Molecular
• Mutation
• Mutation, Missense
• Oncogene Proteins, Fusion (genetics)
• Point Mutation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics)