Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes

Shaoqi Zhang; Shang Lou; Wei Bian; Jun Liu; Rong Wang; Yanan Wang; Yin Zhao; Xiaoqing Zou; Diange Jin; Yue Liang; Jie Sun; Lina Liu

doi:10.1016/j.bbrc.2024.150117

Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes

Biochem Biophys Res Commun. 2024 May 14:719:150117. doi: 10.1016/j.bbrc.2024.150117. Online ahead of print.

Authors

Shaoqi Zhang¹, Shang Lou², Wei Bian², Jun Liu², Rong Wang¹, Yanan Wang², Yin Zhao², Xiaoqing Zou², Diange Jin¹, Yue Liang², Jie Sun³, Lina Liu⁴

Affiliations

¹ Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou, 311121, China.
² Liangzhu Laboratory, Zhejiang University, Hangzhou, 311121, China.
³ Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. Electronic address: jsun1492@zju.edu.cn.
⁴ Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou, 311121, China. Electronic address: linaliu1016@zju.edu.cn.

PMID: 38761635
DOI: 10.1016/j.bbrc.2024.150117

Abstract

The clinical treatment of human acute myeloid leukemia (AML) is rapidly progressing from chemotherapy to targeted therapies led by the BCL-2 inhibitor venetoclax (VEN). Despite its unprecedented success, VEN still encounters clinical resistance. Thus, uncovering the biological vulnerability of VEN-resistant AML disease and identifying effective therapies to treat them are urgently needed. We have previously demonstrated that iron oxide nanozymes (IONE) are capable of overcoming chemoresistance in AML. The current study reports a new activity of IONE in overcoming VEN resistance. Specifically, we revealed an aberrant redox balance with excessive intracellular reactive oxygen species (ROS) in VEN-resistant monocytic AML. Treatment with IONE potently induced ROS-dependent cell death in monocytic AML in both cell lines and primary AML models. In primary AML with developmental heterogeneity containing primitive and monocytic subpopulations, IONE selectively eradicated the VEN-resistant ROS-high monocytic subpopulation, successfully resolving the challenge of developmental heterogeneity faced by VEN. Overall, our study revealed an aberrant redox balance as a therapeutic target for monocytic AML and identified a candidate IONE that could selectively and potently eradicate VEN-resistant monocytic disease.

Keywords: Acute myeloid leukemia; Iron oxide nanoparticles; ROS; Venetoclax.