Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche

Xiaoxin Hao; Hao Gu; Chiqi Chen; Dan Huang; Yuzheng Zhao; Li Xie; Yejun Zou; Hui Sophie Shu; Yaping Zhang; Xiaoxiao He; Xiaoyun Lai; Xiaocui Zhang; Bo O Zhou; Cheng Cheng Zhang; Guo-Qiang Chen; Zhuo Yu; Yi Yang; Junke Zheng

doi:10.1016/j.cmet.2018.11.013

Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche

Cell Metab. 2019 Apr 2;29(4):950-965.e6. doi: 10.1016/j.cmet.2018.11.013. Epub 2018 Dec 20.

Authors

Xiaoxin Hao¹, Hao Gu¹, Chiqi Chen¹, Dan Huang¹, Yuzheng Zhao², Li Xie¹, Yejun Zou², Hui Sophie Shu³, Yaping Zhang¹, Xiaoxiao He¹, Xiaoyun Lai¹, Xiaocui Zhang¹, Bo O Zhou³, Cheng Cheng Zhang⁴, Guo-Qiang Chen¹, Zhuo Yu⁵, Yi Yang⁶, Junke Zheng⁷

Affiliations

¹ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
² Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
³ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: yuzhuo78@shsmu.edu.cn.
⁶ Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Center for Excellence in Brain Science and Intelligence Technology, Institutes of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: yiyang@ecust.edu.cn.
⁷ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: zhengjunke@shsmu.edu.cn.

PMID: 30581117
DOI: 10.1016/j.cmet.2018.11.013

Abstract

The metabolic properties of leukemia-initiating cells (LICs) in distinct bone marrow niches and their relationships to cell-fate determinations remain largely unknown. Using a metabolic imaging system with a highly responsive genetically encoded metabolic sensor, SoNar, we reveal that SoNar-high cells are more glycolytic, enriched for higher LIC frequency, and develop leukemia much faster than SoNar-low counterparts in an MLL-AF9-induced murine acute myeloid leukemia model. SoNar-high cells mainly home to and locate in the hypoxic endosteal niche and maintain their activities through efficient symmetric division. SoNar can indicate the dynamics of metabolic changes of LICs in the endosteal niche. SoNar-high human leukemia cells or primary samples have enhanced clonogenic capacities in vitro or leukemogenesis in vivo. PDK2 fine-tunes glycolysis, homing, and symmetric division of LICs. These findings provide a unique angle for the study of metabolisms in stem cells, and may lead to development of novel strategies for cancer treatment.

Keywords: PDK2; SoNar; endosteal niche; homing; leukemia-initiating cells; metabolic imaging; symmetric division.

Publication types

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

MeSH terms

Animals
Cell Division
Disease Models, Animal
Leukemia, Myeloid, Acute / metabolism*
Leukemia, Myeloid, Acute / pathology*
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Stem Cell Niche*