2. Academic Validation
  3. Mitochondrial oxidative phosphorylation is dispensable for survival of CD34+ chronic myeloid leukemia stem and progenitor cells

Mitochondrial oxidative phosphorylation is dispensable for survival of CD34+ chronic myeloid leukemia stem and progenitor cells

  • Cell Death Dis. 2022 Apr 20;13(4):384. doi: 10.1038/s41419-022-04842-5.
Jin-Song Yan  # 1 2,  Meng-Ying Yang  # 3,  Xue-Hong Zhang  # 4,  Chen-Hui Luo  # 5,  Cheng-Kan Du 3,  Yue Jiang 6,  Xuan-Jia Dong 3,  Zhang-Man Wang 6,  Li-Xue Yang 3,  Yi-Dong Li 7,  Li Xia 8,  Ying Lu 9 10
Affiliations

Affiliations

  • 1 Institute of Dermatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yanjsdmu@dmu.edu.cn.
  • 2 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian, China. yanjsdmu@dmu.edu.cn.
  • 3 Institute of Dermatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • 5 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian, China.
  • 7 Institute of International Medical Science and Technology, Sanda University, Shanghai, China. liyidong2015@163.com.
  • 8 Department of Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China. lixia@shsmu.edu.cn.
  • 9 Institute of Dermatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. stove@shsmu.edu.cn.
  • 10 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian, China. stove@shsmu.edu.cn.
  • # Contributed equally.
PMID: 35444236 DOI: 10.1038/s41419-022-04842-5
Abstract

Chronic myeloid leukemia (CML) are initiated and sustained by self-renewing malignant CD34+ stem cells. Extensive efforts have been made to reveal the metabolic signature of the leukemia stem/progenitor cells in genomic, transcriptomic, and metabolomic studies. However, very little proteomic investigation has been conducted and the mechanism regarding at what level the metabolic program was rewired remains poorly understood. Here, using label-free quantitative proteomic profiling, we compared the signature of CD34+ stem/progenitor cells collected from CML individuals with that of healthy donors and observed significant changes in the abundance of Enzymes associated with aerobic central carbonate metabolic pathways. Specifically, CML stem/progenitor cells expressed increased tricarboxylic acid cycle (TCA) with decreased glycolytic proteins, accompanying by increased Oxidative Phosphorylation (OXPHOS) and decreased glycolysis activity. Administration of the well-known OXPHOS inhibitor metformin eradicated CML stem/progenitor cells and re-sensitized CD34+ CML cells to imatinib in vitro and in patient-derived tumor xenograft murine model. However, different from normal CD34+ cells, the abundance and activity of OXPHOS protein were both unexpectedly elevated with endoplasmic reticulum stress induced by metformin in CML CD34+ cells. The four major aberrantly expressed protein sets, in contrast, were downregulated by metformin in CML CD34+ cells. These data challenged the dependency of OXPHOS for CML CD34+ cell survival and underlined the novel mechanism of metformin. More importantly, it suggested a strong rationale for the use of tyrosine kinase inhibitors in combination with metformin in treating CML.

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