Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia
Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia
复制标题
人急性淋巴细胞白血病GNAO1功能性协同突变的鉴定
DOI：
10.1182/blood.2020005622
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发表时间：
2020
期刊：
影响因子：
20.3
通讯作者：
Feng Haizhong
中科院分区：
文献类型：
--
作者：
Song Lili;Yu Bo;Yang Yi;Liang Jianwei;Zhang Yingwen;Ding Lixia;Wang Tianyi;Wan Xinyu;Yang Xiaomin;Tang Jingyan;Wang Shengyue;Li Benshang;Li Yanxin;Feng Haizhong
白血病的发生以染色体重排和额外的分子破坏为特征，但合作机制仍不清楚。对1对出生后相继发生ETV6-RUNX1(E/R)基因融合的儿童急性淋巴细胞白血病(ALL)单合子双生子进行全外显子测序，确定G蛋白αo1亚基(GNAO1)R209C突变为新的ALL危险基因。此外，GNAO1错义突变仅在所有患者中复发，并与E/R融合相关。GNAO1R209C突变体的异位表达提高了其GTP酶活性，促进了细胞增殖和细胞恶性转化。结合E/R融合，GNAO1R209C突变体通过激活PI3K/Akt/mTOR信号通路促进白血病的发生。反过来，激活mTORC1使p300乙酰转移酶磷酸化，使E/R乙酰化，从而增强GNAO1 R209C的E/R转录活性。因此，我们的研究为GNAO1突变体和E/R融合的功能协同提供了临床证据，表明GNAO1可能成为人类白血病的治疗靶点。
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.