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  3. Therapeutic inhibition of PPARα-HIF1α-PGK1 signaling targets leukemia stem and progenitor cells in acute myeloid leukemia

Therapeutic inhibition of PPARα-HIF1α-PGK1 signaling targets leukemia stem and progenitor cells in acute myeloid leukemia

  • Cancer Lett. 2022 Nov 14;215997. doi: 10.1016/j.canlet.2022.215997.
Hui Zhou 1,  Yuelong Jiang 1,  Yuetin Huang 1,  Mengya Zhong 1,  Dongmei Qin 1,  Chendi Xie 2,  Guangchao Pan 1,  Jinshui Tan 1,  Manman Deng 1,  Haijun Zhao 1,  Yong Zhou 1,  Yuanfang Tang 2,  Qian Lai 1,  Zhihong Fang 1,  Yiming Luo 1,  Yirong Jiang 3,  Bing Xu 4,  Jie Zha 5
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.
  • 3 Department of Hematology, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China. Electronic address: dgjyr0769@163.com.
  • 4 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, China. Electronic address: xubing@xmu.edu.cn.
  • 5 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, China. Electronic address: zhajie@xmu.edu.cn.
PMID: 36396101 DOI: 10.1016/j.canlet.2022.215997
Abstract

Treatment of acute myeloid leukemia (AML) with chemotherapeutic agents fails to eliminate leukemia stem cells (LSC)，and thus patients remain at high risk for relapse. Therefore, the identification of agents that target LSC is an important consideration for the development of new therapies. Enhanced glycolysis in LSC contributes to the aggressiveness of AML, which is difficult to be targeted. In this study, we showed that targeting peroxisome-proliferator-activated receptor α (PPARα), a ligand-activated transcription factor by chiglitazar provided a promising therapeutic approach. We first identified that chiglitazar reduced cell viability and proliferation of the leukemia stem-like cells population in AML. Treatment with chiglitazar blocked the ubiquitination of PPARα and increased its expression, resulting in the inhibition of glucose metabolism and Apoptosis of AML cells. Consistent with its anti-leukemia stem-like cells activity in vitro, chiglitazar treatment in vivo resulted in the significant killing of leukemia stem-like cells as demonstrated in AML patient-derived xenograft (PDX) models. Mechanistically, PPARα overexpression inhibited the expression and promoter activity of PGK1 through blocking HIF1-α interaction on the PGK1 promoter. Thus, we concluded that targeting PPARα may serve as a novel approach for enhancing stem and progenitor cells elimination in AML.

Keywords

Acute myeloid leukemia; Chiglitazar; Glycolysis; HIF1α; Leukemia stem and progenitor cells; PPARα.

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