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Acute myeloid leukemia

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


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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  1. 1.

    Feng Z, Yao Y, Zhou C, Chen F, Wu F, Wei L, et al. Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia. J Hematol Oncol. 2016;9:24.

    Article  Google Scholar 

  2. 2.

    Szer J. The prevalent predicament of relapsed acute myeloid leukemia. Hematol Am Soc Hematol Educ Program. 2012;2012:43–8.

    Article  Google Scholar 

  3. 3.

    Bruedigam C, Bagger FO, Heidel FH, Paine Kuhn C, Guignes S, Song A, et al. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy. Cell Stem Cell. 2014;15:775–90.

    CAS  Article  Google Scholar 

  4. 4.

    Chen CS, Sorensen PH, Domer PH, Reaman GH, Korsmeyer SJ, Heerema NA, et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood. 1993;81:2386–93.

    CAS  Article  Google Scholar 

  5. 5.

    Hilden JM, Dinndorf PA, Meerbaum SO, Sather H, Villaluna D, Heerema NA, et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the children’s oncology group. Blood. 2006;108:441–51.

    CAS  Article  Google Scholar 

  6. 6.

    Mrozek K, Heinonen K, Lawrence D, Carroll AJ, Koduru PR, Rao KW, et al. Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study. Blood. 1997;90:4532–8.

    CAS  Article  Google Scholar 

  7. 7.

    Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22.

    CAS  Article  Google Scholar 

  8. 8.

    Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N, et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004;6:587–96.

    CAS  Article  Google Scholar 

  9. 9.

    Zheng Y, Zhang H, Wang Y, Li X, Lu P, Dong F, et al. Loss of Dnmt3b accelerates MLL-AF9 leukemia progression. Leukemia. 2016;30:2373–84.

    CAS  Article  Google Scholar 

  10. 10.

    Huret JL, Dessen P, Bernheim A. An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia. 2001;15:987–9.

    CAS  Article  Google Scholar 

  11. 11.

    Brabletz T. EMT and MET in metastasis: where are the cancer stem cells? Cancer Cell. 2012;22:699–701.

    CAS  Article  Google Scholar 

  12. 12.

    Gessner A, Thomas M, Castro PG, Buchler L, Scholz A, Brummendorf TH, et al. Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT. Leukemia. 2010;24:1751–9.

    CAS  Article  Google Scholar 

  13. 13.

    Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441:475–82.

    CAS  Article  Google Scholar 

  14. 14.

    Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001;98:2301–7.

    CAS  Article  Google Scholar 

  15. 15.

    Sun Y, Shao L, Bai H, Wang ZZ, Wu WS. Slug deficiency enhances self-renewal of hematopoietic stem cells during hematopoietic regeneration. Blood. 2010;115:1709–17.

    CAS  Article  Google Scholar 

  16. 16.

    Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis. 2011;32:1299–304.

    CAS  Article  Google Scholar 

  17. 17.

    Phillips S, Prat A, Sedic M, Proia T, Wronski A, Mazumdar S, et al. Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation. Stem Cell Rep. 2014;2:633–47.

    CAS  Article  Google Scholar 

  18. 18.

    Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol. 2009;11:694–704.

    CAS  Article  Google Scholar 

  19. 19.

    Liu X, Sun H, Qi J, Wang L, He S, Liu J, et al. Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat Cell Biol. 2013;15:829–38.

    CAS  Article  Google Scholar 

  20. 20.

    Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, et al. SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. Mol Cell. 1999;4:343–52.

    CAS  Article  Google Scholar 

  21. 21.

    Perez-Mancera PA, Gonzalez-Herrero I, Perez-Caro M, Gutierrez-Cianca N, Flores T, Gutierrez-Adan A, et al. SLUG in cancer development. Oncogene. 2005;24:3073–82.

    CAS  Article  Google Scholar 

  22. 22.

    Zhang Z, Zhu P, Zhou Y, Sheng Y, Hong Y, Xiang D, et al. A novel slug-containing negative-feedback loop regulates SCF/c-Kit-mediated hematopoietic stem cell self-renewal. Leukemia. 2017;31:403–13.

    CAS  Article  Google Scholar 

  23. 23.

    Pajor AM, Gangula R, Yao X. Cloning and functional characterization of a high-affinity Na(+)/dicarboxylate cotransporter from mouse brain. Am J Physiol Cell Physiol. 2001;280:C1215–23.

    CAS  Article  Google Scholar 

  24. 24.

    Hole PS, Zabkiewicz J, Munje C, Newton Z, Pearn L, White P, et al. Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling. Blood. 2013;122:3322–30.

    CAS  Article  Google Scholar 

  25. 25.

    Paul TA, Bies J, Small D, Wolff L. Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML. Blood. 2010;115:3098–108.

    CAS  Article  Google Scholar 

  26. 26.

    Chan WI, Huntly BJ. Leukemia stem cells in acute myeloid leukemia. Semin Oncol. 2008;35:326–35.

    CAS  Article  Google Scholar 

  27. 27.

    Wei CR, Liu J, Yu XJ. Targeting SLUG sensitizes leukemia cells to ADR-induced apoptosis. Int J Clin Exp Med. 2015;8:22139–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Lataillade JJ, Pierre-Louis O, Hasselbalch HC, Uzan G, Jasmin C, Martyre MC, et al. Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence. Blood. 2008;112:3026–35.

    CAS  Article  Google Scholar 

  29. 29.

    Chen X, Tsukaguchi H, Chen XZ, Berger UV, Hediger MA. Molecular and functional analysis of SDCT2, a novel rat sodium-dependent dicarboxylate transporter. J Clin Invest. 1999;103:1159–68.

    CAS  Article  Google Scholar 

  30. 30.

    Ma Y, Bai XY, Du X, Fu B, Chen X. NaDC3 induces premature cellular senescence by promoting transport of krebs cycle intermediates, increasing NADH, and exacerbating oxidative damage. J Gerontol A Biol Sci Med Sci. 2016;71:1–12.

    CAS  Article  Google Scholar 

  31. 31.

    Chen WL, Wang YY, Zhao A, Xia L, Xie G, Su M, et al. Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of acute myeloid leukemia with therapeutic potential. Cancer Cell. 2016;30:779–91.

    Article  Google Scholar 

  32. 32.

    Tamura K, Makino A, Hullin-Matsuda F, Kobayashi T, Furihata M, Chung S, et al. Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism. Cancer Res. 2009;69:8133–40.

    CAS  Article  Google Scholar 

  33. 33.

    Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia A, Sanchez ML, Orfao A, Flores T, et al. Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway. Blood. 2002;100:1274–86.

    CAS  Article  Google Scholar 

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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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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).

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