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

Xiaoya Cai; Ying Liu; Huimin Li; Yimei Que; Min Xiao; Ying Wang; Xiong Wang; Dengju Li

doi:10.1007/s00277-024-05706-y

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

Ann Hematol. 2024 Mar 23. doi: 10.1007/s00277-024-05706-y. Online ahead of print.

Authors

Xiaoya Cai¹, Ying Liu¹, Huimin Li¹, Yimei Que¹, Min Xiao¹, Ying Wang¹, Xiong Wang², Dengju Li³

Affiliations

¹ Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Clinical Laboratory, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangxiong@tjh.tjmu.edu.cn.
³ Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. lidengju@tjh.tjmu.edu.cn.

PMID: 38519605
DOI: 10.1007/s00277-024-05706-y

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 DNMT3A^R882H AML patients. Therefore, we further investigated the therapeutic effect of XPO1 inhibition on DNMT3A^R882H AML. Three types of DNMT3A^R882H AML cell lines were generated, and XPO1 was significantly upregulated in all DNMT3A^R882H 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 DNMT3A^R882H cells than WT cells. Selinexor also significantly inhibited the proliferation of subcutaneous tumors in DNMT3A^R882H 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 DNMT3A^WT/DNMT3A^R882H AML cells. In conclusion, our work reveals that selinexor displays anti-leukemia efficacy against DNMT3A^R882H AML via downregulating glutathione pathway. Combination of selinexor and BSO provides novel therapeutic strategy for AML treatment.

Keywords: Acute myeloid leukaemia; DNA methyltransferase 3A; exportin-1; glutathione.