AUTHOR=Li Mengya , Liu Yu , Liu Yajun , Yang Lu , Xu Yan , Wang Weiqiong , Jiang Zhongxing , Liu Yanfang , Wang Shujuan , Wang Chong 

TITLE=Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.724435

DOI=10.3389/fonc.2021.724435

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>The prognosis of acute myeloid leukemia (AML) with a normal karyotype is highly heterogonous, and the current risk stratification is still insufficient to differentiate patients from high-risk to standard-risk. Changes in some genetic profiles may contribute to the poor prognosis of AML. Although the prognostic value of G protein subunit alpha 15 (<italic>GNA15</italic>) in AML has been reported based on the GEO (Gene Expression Omnibus) database, the prognostic significance of <italic>GNA15</italic> has not been verified in clinical samples. The biological functions of <italic>GNA15</italic> in AML development remain open to investigation. This study explored the clinical significance, biological effects and molecular mechanism of <italic>GNA15</italic> in AML.</p></sec><sec><title>Methods</title><p>Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression level of <italic>GNA15</italic> in blasts of bone marrow specimens from 154 newly diagnosed adult AML patients and 26 healthy volunteers. AML cell lines, Kasumi-1 and SKNO-1, were used for lentiviral transfection. Cell Counting Kit-8 (CCK8) and colony formation assays were used to determine cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. The relevant signaling pathways were evaluated by Western blot. The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis. Xenograft tumor mouse model was used for <italic>in vivo</italic> experiments.</p></sec><sec><title>Results</title><p>The expression of <italic>GNA15</italic> in adult AML was significantly higher than that in healthy individuals. Subjects with high <italic>GNA15</italic> expression showed lower overall survival and relapse-free survival in adult AML with normal karyotype. High <italic>GNA15</italic> expression was independently correlated with a worse prognosis in multivariate analysis. Knockdown of <italic>GNA15</italic> inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. <italic>GNA15</italic>-knockdown induced down-regulation of p-P38 MAPK and its downstream p-MAPKAPK2 and p-CREB. Rescue assays confirmed that P38 MAPK signaling pathway was involved in the inhibition of proliferation mediated by GNA15 knockdown.</p></sec><sec><title>Conclusions</title><p>In summary, <italic>GNA15</italic> was highly expressed in adult AML, and high <italic>GNA15</italic> expression was independently correlated with a worse prognosis in adult AML with normal karyotype. Knockdown of <italic>GNA15</italic> inhibited the proliferation of AML regulated by the P38 MAPK signaling pathway. Therefore, <italic>GNA15</italic> may serve as a potential prognostic marker and a therapeutic target for AML in the future.</p></sec>