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Acute myeloid leukemia

Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway

Leukemia volume 34, pages 380–390 (2020)Cite this article

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Abstract

Leukemia stem cells (LSCs) are the rare populations of acute myeloid leukemia (AML) cells that are able to initiate, maintain, and propagate AML. Targeting LSCs is a promising approach for preventing AML relapse and improving long-term outcomes. While Slug, a zinc-finger transcription repressor, negatively regulates the self-renewal of normal hematopoietic stem cells, its functions in AML are still unknown. We report here that Slug promotes leukemogenesis and its loss impairs LSC self-renewal and delays leukemia progression. Mechanistically, Slc13a3, a direct target of Slug in LSCs, restricts the self-renewal of LSCs and markedly prolongs recipient survival. Genetic or pharmacological inhibition of SLUG or forced expression of Slc13a3 suppresses the growth of human AML cells. In conclusion, our studies demonstrate that Slug differentially regulates self-renewal of LSCs and normal HSCs, and both Slug and Slc13a3 are potential therapeutic targets of LSCs.

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Acknowledgements

This research was supported in part by an NIDDK/NIH grant (5R01DK090478-06). ZZ was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and the Natural Science Foundation of Shanghai (Grant no. 18ZR1414900). LL was supported by a grant from the National Nature Science Foundation of China (no. 81500133).

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Authors and Affiliations

  1. School of Life Sciences, Shanghai University, 200444, Shanghai, China

    Zhonghui Zhang & Chen Wu

  2. Division of Hematology/Oncology, Department of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Zhonghui Zhang, Guoshu Yin, Pei Zhu, Yalu Zhou, Yuanfan Hong & Wen-Shu Wu

  3. Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China

    Lei Li

  4. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China

    Guoshu Yin

  5. Department of Pathology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Hongyu Ni

  6. Division of Hematology/Oncology, Department of Medicine and The University of Florida, Cancer/Genetics Research Complex, Florida, FL, 32610, USA

    Zhijian Qian

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  1. Zhonghui Zhang
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Contributions

Contribution: ZZ and WSW were responsible for experimental design and data analysis. ZZ, LL, CW, GY, PZ, and YH performed experiments. YZ performed microarray analyses. ZZ and WSW wrote the manuscript. ZQ and NH provided key materials and suggestions for experimental design. WSW provided supervision.

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Correspondence to Wen-Shu Wu.

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Zhang, Z., Li, L., Wu, C. et al. Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway. Leukemia 34, 380–390 (2020). https://doi.org/10.1038/s41375-019-0566-x

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