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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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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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
Experimental Hematology & Oncology (2021)