Cytohesin-4/ARF6 facilitates the progression of acute myeloid leukemia through activating PIK3R5/PI3K/AKT pathway

Xiao-Fen Qiu; Cheng-Ming He; Yan-Mei Zeng; Xiao-Ling Deng; Guo-Lin Liang; Ming-Xing Zhong; Min Zou; Xiu-Juan Xiong; Jing-Dong Zhang; Yan Ye; Qing Niu; Xiao-Li Chen

doi:10.1016/j.isci.2025.112634

Cytohesin-4/ARF6 facilitates the progression of acute myeloid leukemia through activating PIK3R5/PI3K/AKT pathway

iScience. 2025 May 12;28(6):112634. doi: 10.1016/j.isci.2025.112634. eCollection 2025 Jun 20.

Authors

Xiao-Fen Qiu^{1

2}, Cheng-Ming He¹, Yan-Mei Zeng^{1

2}, Xiao-Ling Deng^{1

2}, Guo-Lin Liang^{1

2}, Ming-Xing Zhong¹, Min Zou¹, Xiu-Juan Xiong³, Jing-Dong Zhang¹, Yan Ye^{1

2}, Qing Niu⁴, Xiao-Li Chen^{1

2}

Affiliations

¹ Jiangxi Health Commission Key Laboratory of Leukemia, the Affiliated Ganzhou Hospital, Jiangxi Medical College, Nanchang University, Ganzhou 341000, China.
² Ganzhou Key Laboratory of Molecular Medicine, the Affiliated Ganzhou Hospital, Jiangxi Medical College, Nanchang University, Ganzhou 341000, China.
³ Department of Pathology, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
⁴ State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.

Abstract

In silico analysis revealed an elevated expression of cytohesin-4 (CYTH4) in acute myeloid leukemia (AML) cells, correlating with a poorer prognosis for AML patients. However, its role in AML is not fully understood. Our study using loss-of-function assays identified CYTH4 as an oncogene promoting leukemogenesis. Silencing CYTH4 in MV4-11 and THP-1 cells reduced cell proliferation and colony formation, and induced apoptosis and cell-cycle arrest at G0/G1, whereas overexpression had no significant impact. CYTH4 silencing also increased chemosensitivity to cytarabine. In a THP-1 xenograft model, CYTH4 silencing slowed AML progression and reduced leukemic cell homing and infiltration. Mechanistically, CYTH4 silencing inhibited PI3K/AKT pathway by lowering PIK3R5 and decreased ARF6-GTP levels, as confirmed by pull-down assays. Overexpression of PIK3R5 and AKT activation via SC-79 successfully countered the cellular dysfunctions from CYTH4 silencing. Thus, CYTH4 may play a role in AML progression, and targeting its pathway could be a promising anti-leukemic treatment strategy.

Keywords: Cancer; Cell biology.