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XPO1 inhibition displays anti-leukemia efficacy against DNMT3A-mutant acute myeloid leukemia via downregulating glutathione pathway

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Abstract

Acute myeloid leukemia (AML) patients with DNA methyltransferase 3A (DNMT3A) mutation display poor prognosis, and targeted therapy is not available currently. Our previous study identified increased expression of Exportin1 (XPO1) in DNMT3AR882H AML patients. Therefore, we further investigated the therapeutic effect of XPO1 inhibition on DNMT3AR882H AML. Three types of DNMT3AR882H AML cell lines were generated, and XPO1 was significantly upregulated in all DNMT3AR882H cells compared with the wild-type (WT) cells. The XPO1 inhibitor selinexor displayed higher potential in the inhibition of proliferation, promotion of apoptosis, and blockage of the cell cycle in DNMT3AR882H cells than WT cells. Selinexor also significantly inhibited the proliferation of subcutaneous tumors in DNMT3AR882H AML model mice. Primary cells with DNMT3A mutations were more sensitive to selinexor in chemotherapy-naive AML patients. RNA sequencing of selinexor treated AML cells revealed that the majority of metabolic pathways were downregulated after selinexor treatment, with the most significant change in the glutathione metabolic pathway. Glutathione inhibitor L-Buthionine-(S, R)-sulfoximine (BSO) significantly enhanced the apoptosis-inducing effect of selinexor in DNMT3AWT/DNMT3AR882H AML cells. In conclusion, our work reveals that selinexor displays anti-leukemia efficacy against DNMT3AR882H AML via downregulating glutathione pathway. Combination of selinexor and BSO provides novel therapeutic strategy for AML treatment.

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Data availability

This study provides all raw data free of charge. If you have any questions, please contact xiaoyacai6231@163.com. The RNA-seq raw data of cell lines to the GSA database( https://ngdc.cncb.ac.cn/gsub/ ), and the assigned accession of the submission is HRA005049.

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Acknowledgments

The National Natural Science Foundation of China [82270177] and Hubei Chen Xiaoping science and Technology Development Foundation [CXPJJH12000009-112].

Institutional review board

The study was conducted by the Declaration of Helsinki, and approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (TJIRB20230228 and 2023.2.10). The animal study protocol was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology ([2022]IACUC Number: 3300 and 2022.2.1).

Funding

This work was supported by the National Natural Science Foundation of China [82270177] and Hubei Chen Xiaoping Science and Technology Development Foundation [CXPJJH12000009-112].

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Authors and Affiliations

  1. Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiaoya Cai, Ying Liu, Huimin Li, Yimei Que, Min Xiao, Ying Wang & Dengju Li

  2. Department of Clinical Laboratory, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiong Wang

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  1. Xiaoya Cai
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  2. Ying Liu
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  3. Huimin Li
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Contributions

XC, DL and XW conceptualized this study. XC completed data curation. YL, HL, and XW con-ducted the investigation. XC, DL, YL, YQ, and XW completed the methodology. DL was re-sponsible for project administration. MX and YW were in charge of the software. XC wrote the original draft. DL wrote, reviewed, and edited the manuscript. All authors contributed to the ar-ticle and approved the submitted version.

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Correspondence to Xiong Wang or Dengju Li.

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Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient(s) to publish this paper.

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Figure S1: Differential genes expression analysis after selinexor treatment. (PDF 367 kb)

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Cai, X., Liu, Y., Li, H. et al. XPO1 inhibition displays anti-leukemia efficacy against DNMT3A-mutant acute myeloid leukemia via downregulating glutathione pathway. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05706-y

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