Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia

Chendi Xie; Hui Zhou; Dongmei Qin; Huijian Zheng; Yuanfang Tang; Wenjuan Li; Jie Zhou; Long Liu; Xinxin Yu; Hongpeng Duan; Yong Zhou; Zhifeng Li; Zhihong Fang; Yiming Luo; Bing Z Carter; Bing Xu; Jie Zha

doi:10.1038/s41419-023-06075-6

Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia

Cell Death Dis. 2023 Aug 29;14(8):573. doi: 10.1038/s41419-023-06075-6.

Authors

Chendi Xie^#^{1

2

3}, Hui Zhou^#^{1

2}, Dongmei Qin^{1

2}, Huijian Zheng⁴, Yuanfang Tang^{1

2

3}, Wenjuan Li^{1

2

3}, Jie Zhou^{1

2}, Long Liu^{1

2}, Xinxin Yu^{1

2}, Hongpeng Duan^{1

2}, Yong Zhou^{1

2}, Zhifeng Li^{1

2}, Zhihong Fang^{1

2}, Yiming Luo^{1

2}, Bing Z Carter⁵, Bing Xu^{6

7}, Jie Zha^{8

9}

Affiliations

¹ Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China.
² Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, China.
³ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.
⁴ School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China.
⁵ Section of Molecular Hematology and Therapy, Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA. bicarter@mdanderson.org.
⁶ Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China. xubing@xmu.edu.cn.
⁷ Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, China. xubing@xmu.edu.cn.
⁸ Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China. zhajie@xmu.edu.cn.
⁹ Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, China. zhajie@xmu.edu.cn.

^# Contributed equally.

Abstract

Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34⁺ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML progression in patient-derived xenograft (PDX) mouse models. Mechanistically, chiglitazar-mediated PPARα activation inhibited the transcriptional activity of the PIK3AP1 gene promoter and down-regulated the PI3K/Akt signaling pathway and anti-apoptotic Bcl-2 proteins, leading to cell proliferation inhibition and apoptosis induction, which was synergized with venetoclax. These findings suggest that combinatorial Bcl-2 inhibition and PPARα activation selectively eliminates AML cells in vivo and vitro, representing an effective therapy for patients with relapsed and refractory AML.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Humans
Mice
PPAR alpha*
Phosphatidylinositol 3-Kinases*
Stem Cells

Substances

chiglitazar
venetoclax
PPAR alpha
Phosphatidylinositol 3-Kinases