Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ACUTE MYELOID LEUKEMIA

Mitochondrial regulation of GPX4 inhibition–mediated ferroptosis in acute myeloid leukemia

Leukemia volume 38, pages 729–740 (2024)Cite this article

Subjects

A Correction to this article was published on 08 March 2024

This article has been updated

Abstract

Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti–lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition–mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition–mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: GPX4 is a potential therapeutic target in AML.
Fig. 2: The pharmacological inhibition of GPX4 induces ferroptosis in AML.
Fig. 3: The genetic knockdown of GPX4 induces ferroptosis in AML in vitro and in vivo.
Fig. 4: Mitochondrial lipid peroxidation and electron transport chain complexes regulate AML cell ferroptosis.
Fig. 5: GPX4 inhibition–mediated ferroptosis is synergistically enhanced by ClpP hyperactivation.

Similar content being viewed by others

Data availability

All data generated during this study are included in this published article and its supplementary files. Additional data are available from the corresponding author upon reasonable request.

Change history

References

  1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program: Cancer Stat Facts: Leukemia — Acute Myeloid Leukemia (AML) 2022 [Available from: https://seer.cancer.gov/statfacts/html/amyl.html.

  2. Ganzel C, Sun Z, Cripe LD, Fernandez HF, Douer D, Rowe JM, et al. Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience. Am J Hematol. 2018;93:1074–81.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kropp EM, Li Q. Mechanisms of resistance to targeted therapies for relapsed or refractory acute myeloid leukemia. Exp Hematol. 2022;111:13–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ong F, Kim K, Konopleva MY. Venetoclax resistance: mechanistic insights and future strategies. Cancer Drug Resist. 2022;5:380–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22:381–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575:693–8.

    Article  CAS  PubMed  Google Scholar 

  10. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593:586–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wu S, Mao C, Kondiparthi L, Poyurovsky MV, Olszewski K, Gan B. A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria. Proc Natl Acad Sci USA. 2022;119:e2121987119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Muller C, Zandkarimi F, et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent Sci. 2020;6:41–53.

    Article  CAS  PubMed  Google Scholar 

  13. Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F, et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol. 2020;16:1351–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Weitzel F, Ursini F, Wendel A. Phospholipid hydroperoxide glutathione peroxidase in various mouse organs during selenium deficiency and repletion. Biochim Biophys Acta. 1990;1036:88–94.

    Article  CAS  PubMed  Google Scholar 

  15. Hole PS, Darley RL, Tonks A. Do reactive oxygen species play a role in myeloid leukemias? Blood. 2011;117:5816–26.

    Article  CAS  PubMed  Google Scholar 

  16. Lopes M, Duarte TL, Teles MJ, Mosteo L, Chacim S, Aguiar E, et al. Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications. Blood Adv. 2021;5:3102–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu Y, Xie Y, Cao L, Yang L, Yang M, Lotze MT, et al. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol. 2015;2:e1054549.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ye F, Chai W, Xie M, Yang M, Yu Y. Cao L, et al. HMGB1 regulates erastin-induced ferroptosis via RAS-JNK/p38 signaling in HL-60/NRAS(Q61L) cells. Am J Cancer Res. 2019;9:730–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yusuf RZ, Saez B, Sharda A, van Gastel N, Yu VWC, Baryawno N, et al. Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers. Blood. 2020;136:1303–16.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Birsen R, Larrue C, Decroocq J, Johnson N, Guiraud N, Gotanegre M, et al. APR-246 induces early cell death by ferroptosis in acute myeloid leukemia. Haematologica. 2022;107:403–16.

    Article  CAS  PubMed  Google Scholar 

  21. Pardieu B, Pasanisi J, Ling F, Dal Bello R, Penneroux J, Su A, et al. Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia. Leukemia. 2022;36:1585–95.

    Article  CAS  PubMed  Google Scholar 

  22. Akiyama H, Carter BZ, Andreeff M, Ishizawa J. Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia. Cells. 2023;12:1128.

  23. Sabatier M, Birsen R, Lauture L, Mouche S, Angelino P, Dehairs J, et al. C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia. Cancer Discov. 2023;13:1720–47.

  24. Shimada K, Bachman JA, Muhlich JL, Mitchison TJ. shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data. Elife. 2021;10:e57116.

  25. Zhou N, Bao J. FerrDb: a manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations. Database. 2020;2020:baaa021.

  26. Zhou N, Yuan X, Du Q, Zhang Z, Shi X, Bao J, et al. FerrDb V2: update of the manually curated database of ferroptosis regulators and ferroptosis-disease associations. Nucleic Acids Res. 2023;51:D571–D82.

    Article  CAS  PubMed  Google Scholar 

  27. Cui C, Yang F, Li Q. Post-Translational Modification of GPX4 is a Promising Target for Treating Ferroptosis-Related Diseases. Front Mol Biosci. 2022;9:901565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kramer MH, Zhang Q, Sprung R, Day RB, Erdmann-Gilmore P, Li Y, et al. Proteomic and phosphoproteomic landscapes of acute myeloid leukemia. Blood. 2022;140:1533–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wei J, Xie Q, Liu X, Wan C, Wu W, Fang K, et al. Identification the prognostic value of glutathione peroxidases expression levels in acute myeloid leukemia. Ann Transl Med. 2020;8:678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shi ZZ, Tao H, Fan ZW, Song SJ, Bai J. Prognostic and Immunological Role of Key Genes of Ferroptosis in Pan-Cancer. Front Cell Dev Biol. 2021;9:748925.

    Article  PubMed  PubMed Central  Google Scholar 

  32. National Cancer Institute. Genomic Data Commons Data Portal 2022. https://portal.gdc.cancer.gov/.

  33. Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562:526–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jayavelu AK, Wolf S, Buettner F, Alexe G, Haupl B, Comoglio F, et al. The proteogenomic subtypes of acute myeloid leukemia. Cancer Cell. 2022;40:301–17.e12.

    Article  CAS  PubMed  Google Scholar 

  35. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Eaton JK, Furst L, Ruberto RA, Moosmayer D, Hilpmann A, Ryan MJ, et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat Chem Biol. 2020;16:497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kloditz K, Fadeel B. Three cell deaths and a funeral: macrophage clearance of cells undergoing distinct modes of cell death. Cell Death Discov. 2019;5:65.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Simonovic M, Puppala AK. On elongation factor eEFSec, its role and mechanism during selenium incorporation into nascent selenoproteins. Biochim Biophys Acta Gen Subj. 2018;1862:2463–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, et al. Inhibiting the system x(C)(-)/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat Commun. 2017;8:14844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sun MG, Williams J, Munoz-Pinedo C, Perkins GA, Brown JM, Ellisman MH, et al. Correlated three-dimensional light and electron microscopy reveals transformation of mitochondria during apoptosis. Nat Cell Biol. 2007;9:1057–65.

    Article  CAS  PubMed  Google Scholar 

  43. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.

    Article  CAS  PubMed  Google Scholar 

  44. Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W, et al. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem. 2003;278:37832–9.

    Article  CAS  PubMed  Google Scholar 

  45. Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, Jitkova Y, et al. Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer Cell. 2019;35:721–37.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jacques S, van der Sloot AM, Huard CC, Coulombe-Huntington J, Tsao S, Tollis S, et al. Imipridone Anticancer Compounds Ectopically Activate the ClpP Protease and Represent a New Scaffold for Antibiotic Development. Genetics. 2020;214:1103–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Conrad M, Proneth B. Selenium: Tracing Another Essential Element of Ferroptotic Cell Death. Cell Chem Biol. 2020;27:409–19.

    Article  CAS  PubMed  Google Scholar 

  48. Molina JR, Sun Y, Protopopova M, Gera S, Bandi M, Bristow C, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018;24:1036–46.

    Article  CAS  PubMed  Google Scholar 

  49. Oh SJ, Ikeda M, Ide T, Hur KY, Lee MS. Mitochondrial event as an ultimate step in ferroptosis. Cell Death Discov. 2022;8:414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of Mitochondria in Ferroptosis. Mol Cell. 2019;73:354–63.e3.

    Article  CAS  PubMed  Google Scholar 

  51. To TL, Cuadros AM, Shah H, Hung WHW, Li Y, Kim SH, et al. A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering. Cell. 2019;179:1222–38.e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Magtanong L, Mueller GD, Williams KJ, Billmann M, Chan K, Armenta DA, et al. Context-dependent regulation of ferroptosis sensitivity. Cell Chem Biol. 2022;29:1409–18.e6.

  53. Dixon SJ, Pratt DA. Ferroptosis: A flexible constellation of related biochemical mechanisms. Mol Cell. 2023;83:1030–42.

    Article  CAS  PubMed  Google Scholar 

  54. Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, et al. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal. 2016;9:ra17.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chen MS, Wang SF, Hsu CY, Yin PH, Yeh TS, Lee HC, et al. CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2alpha-ATF4 pathway. Oncotarget. 2017;8:114588–602.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wang Y, Hekimi S. Understanding Ubiquinone. Trends Cell Biol. 2016;26:367–78.

    Article  CAS  PubMed  Google Scholar 

  57. Canli O, Alankus YB, Grootjans S, Vegi N, Hultner L, Hoppe PS, et al. Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood. 2016;127:139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Altamura S, Vegi NM, Hoppe PS, Schroeder T, Aichler M, Walch A, et al. Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis. Haematologica. 2020;105:937–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hu Q, Zhang Y, Lou H, Ou Z, Liu J, Duan W, et al. GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis. Cell Death Dis. 2021;12:706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhao J, Jia Y, Mahmut D, Deik AA, Jeanfavre S, Clish CB, et al. Human hematopoietic stem cell vulnerability to ferroptosis. Cell. 2023;186:732–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Imai H, Hirao F, Sakamoto T, Sekine K, Mizukura Y, Saito M, et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun. 2003;305:278–86.

    Article  CAS  PubMed  Google Scholar 

  62. Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003;34:496–502.

    Article  CAS  PubMed  Google Scholar 

  63. Liu H, Forouhar F, Seibt T, Saneto R, Wigby K, Friedman J, et al. Characterization of a patient-derived variant of GPX4 for precision therapy. Nat Chem Biol. 2022;18:91–100.

    Article  PubMed  Google Scholar 

  64. Boettcher S, Miller PG, Sharma R, McConkey M, Leventhal M, Krivtsov AV, et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science. 2019;365:599–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Carter BZ, Mak PY, Tao W, Zhang Q, Ruvolo V, Kuruvilla VM, et al. Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic-Resistant AML and AML Stem Cells. Mol Cancer Ther. 2022;21:879–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Kenneth Dunner Jr., (MD Anderson Cancer Center High Resolution Electron Microscopy Facility) for assisting with transmission electron microscopy experiments, Manu M Sebastian (MD Anderson Cancer Center Department of Veterinary Medicine and Surgery) for assisting with in vivo experiments, M.L.P. 2nd was supported by the 1R25CA240137 UPWARDS Training Program and the CPRIT Research Training Award CPRIT Training Program (RP210028), Steffen Boettcher (University of Zurich, Zurich, Switzerland) for providing cell lines, Joseph A Munch (MD Anderson Cancer Center Science Medical Library) for editing the manuscript, and Boyi Gan (MD Anderson Cancer Center Department of Experimental Radiation Oncology) for reviewing the manuscript. This work was supported in part by Japan Cancer Society Relay For Life My Oncology Dream Award (HA), The Mochida Memorial Foundation for Medical and Pharmaceutical Research (HA), The Uehara Memorial Foundation Research Fellowship (HA), TRIUMPH fellowship in the Cancer Prevention Research Institution of Texas (CPRIT) Training Program RP210028 (EA), Paul & Mary Haas Chair in Genetics (MA), NIH/NCI R41 CA275631 (MA), FDA R01 FD006118 (MA and JI) Leukemia SPORE P50 CA100632 Development Research Program (MA and JI), MD Anderson Multidisciplinary Research Program (MA and JI), MD Anderson Cancer Center Institutional Research Grant (JI), the Department of Defense CA220581 (JI), New Investigator Research Grant Program from Leukemia Research Foundation (JI), and various donor funds (MA). Part of the study was performed in the Flow Cytometry & Cellular Imaging Core Facility and High Resolution Electron Microscopy Facility at MD Anderson Cancer Center, which is supported in part by NCI Cancer Center Support Grant P30CA16672. The animal study was supported in part by the MD Anderson Cancer Center Support Grant CA016672 including animal housing and care in the Research Animal Support Facility (RASF). Imipridones ONC201 and ONC212 were kindly provided from Chimerix (Durham, NC).

Author information

Authors and Affiliations

  1. Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Hiroki Akiyama, Ran Zhao, Lauren B. Ostermann, Samar J. Yazdani, Arman Moayed, Malcolm L. Pryor II, Sandeep Slngh, Natalia Baran, Edward Ayoub, Yuki Nishida, Po Yee Mak, Vivian R. Ruvolo, Bing Z. Carter, Michael Andreeff & Jo Ishizawa

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ziyi Li

  3. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Matthew Tcheng & Aaron D. Schimmer

Authors
  1. Hiroki Akiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ran Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lauren B. Ostermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ziyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthew Tcheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samar J. Yazdani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arman Moayed
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Malcolm L. Pryor II
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sandeep Slngh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Natalia Baran
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Edward Ayoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yuki Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Po Yee Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vivian R. Ruvolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Bing Z. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Aaron D. Schimmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michael Andreeff
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jo Ishizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HA, MA, and JI designed and conceptualized the study. HA and JI designed experiments. HA, RZ, MT, SJY, AM, MLPII, and NB performed in vitro experiments and analyzed data. HA, RZ, LBO, SJY, AM, and SS performed in vivo experiments and analyzed data. HA, RZ, MT, SS, NB, ADS, MA, and JI interpreted the data and draw the conclusions. YN, PYM, and VRR provided technical and material supports of experiments. ZL and EA performed statistical analyses. HA and JI wrote the manuscript. MT, BZC, ADS, MA, and JI reviewed/revised the manuscript. All authors read and approved the final paper.

Corresponding author

Correspondence to Jo Ishizawa.

Ethics declarations

Competing interests

MA is a stockholder of Chimerix. JI, MA, and ADS have filed invention disclosure forms related to the use of imipridones in cancers. ADS has received research funding from Takeda Pharmaceuticals, BMS and Medivir AB, and consulting fees/honorarium from Takeda, Novartis, Jazz, and Otsuka Pharmaceuticals. ADS is named on a patent application for the use of DNT cells to treat AML. ADS is a member of the Medical and Scientific Advisory Board of the Leukemia and Lymphoma Society of Canada.

Ethics approval and consent to participate

The mouse studies were performed following the guidelines approved by the Institutional Animal Care and Use Committees at MD Anderson Cancer Center. Primary samples were obtained from AML patients and hematopoietic stem cell donors after acquiring written informed consent following MD Anderson Cancer Center Institutional Review Board protocol and in accordance with the Declaration of Helsinki.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: In this article the funding from M.L.P. 2nd was supported by the 1R25CA240137 UPWARDS Training Program and the CPRIT Research Training Award CPRIT Training Program (RP210028) was omitted.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akiyama, H., Zhao, R., Ostermann, L.B. et al. Mitochondrial regulation of GPX4 inhibition–mediated ferroptosis in acute myeloid leukemia. Leukemia 38, 729–740 (2024). https://doi.org/10.1038/s41375-023-02117-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-023-02117-2

Search

Advanced search

Quick links