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ARHGAP4 promotes leukemogenesis in acute myeloid leukemia by inhibiting DRAM1 signaling

Oncogene volume 42, pages 2547–2557 (2023)Cite this article

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Abstract

Rho GTPase-activating protein 4 (ARHGAP4) is an important Rho family GTPase-activating protein that is strongly associated with the onset and progression of some tumors. We found that ARHGAP4 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) patients and are associated with a poor prognosis. ARHGAP4 knockdown significantly impairs viability and colony formation capacity and induces apoptosis in AML cells. Further results demonstrate that ARHGAP4 deletion impairs AML progression in vivo. Interestingly, DRAM1 signaling is significantly activated in AML cells with ARHGAP4 knockdown. Our results also indicated that ARHGAP4 might function in AML cells by binding with p53 to inhibit DRAM1. Moreover, knockdown of DRAM1 rescues the defects of ARHGAP4 in AML cells. This newly described role of the ARHGAP4/DRAM1 axis in regulating AML progression may have important therapeutic implications.

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Fig. 1: ARHGAP4 expression levels are significantly increased in patients with AML.
Fig. 2: ARHGAP4 promotes cell proliferation and suppresses apoptosis in vitro.
Fig. 3: Arhgap4 significantly supports AML progression.
Fig. 4: Arhgap4 knockdown significantly decelerates AML tumorigenesis in NOD/SCID mice.
Fig. 5: P53/DRAM1 signal dynamics during the response to ARHGAP4 deletion.
Fig. 6: DRAM1 is involved in the pathway with the development of AML.

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Data availability

The RNA-seq data discussed in this publication have been deposited in BioProject database with the accession code PRJNA956986. The datasets obtained and analyzed during the current study were made available from the corresponding authors through request.

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Acknowledgements

We thank Prof. Jinyong Wang for gifting CD45.1 mice, Yang Liu and Haiying Ran for technical support in flow cytometry.

Funding

This work was supported by grants from the Scientific Research Project of PLA (2018XLC306); Science Foundations of Army Medical Center (No.2019CXJSB020); The Key Program of the Natural Science Foundation of China (No. 81930090).

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Author notes

  1. These authors contributed equally: Yan Qi, Mengjia Hu, Changhao Han.

Authors and Affiliations

  1. Department of Hematology, Daping Hospital, Third Military Medical University, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, China

    Yan Qi, Changhao Han, Jin Wang, Yuanting She, Meijuan Zhang, Jing Zhang, Zhongyue Zhao, Huan Xie & Dongfeng Zeng

  2. State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Gaotanyan Street 30, Chongqing, 400038, China

    Mengjia Hu, Fang Chen, Song Wang, Mo Chen & Junping Wang

  3. Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Hui Guo

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Contributions

YQ, MH and CH designed and performed the experiments, analyzed the data and wrote the paper; FC, YS and MZ contributed to animal experiments and data analysis; JZ, MC and SW contributed to the in vitro experiments; HX and ZZ provided human samples; JW and HG contributed to the initial experimental design and discussed the manuscript; JW and DZ conceived and supervised the study, analyzed the data, and wrote and revised the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Junping Wang or Dongfeng Zeng.

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Qi, Y., Hu, M., Han, C. et al. ARHGAP4 promotes leukemogenesis in acute myeloid leukemia by inhibiting DRAM1 signaling. Oncogene 42, 2547–2557 (2023). https://doi.org/10.1038/s41388-023-02770-y

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