Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

Author:

Long Huideng1,Hou Yue1ORCID,Li Jun1,Song Chunhua23,Ge Zheng1ORCID

Affiliation:

1. Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, China

2. Hershey Medical Center, Pennsylvania State University Medical College, Hershey, PA 17033, USA

3. Division of Hematology, The Ohio State University Wexner Medical Center, The James Cancer Hospital, Columbus, OH 43210, USA

Abstract

Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of XPO1 and eIF4E was elevated in AML patient cohorts, respectively. XPO1 and elF4E overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML.

Funder

The National Natural Science Foundation of China

Jiangsu Province “333” project

Medical research key projects Jiangsu Commission of Health

Jiangsu Provincial Medical Key Discipline (Laboratory) Cultivation Unit

Milstein Medical Asian American Partnership (MMAAP) Foundation Research Project Award in Hematology

Postgraduate Research & Practice Innovation Program of Jiangsu Province

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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