Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
All data generated during this study are included either in article or in the additional files. RNA-seq data are uploaded to GEO database.
Gugliucci A. Polyamines as clinical laboratory tools. Clin Chim Acta. 2004;344:23–35.
Seiler N, Delcros JG, Moulinoux JP. Polyamine transport in mammalian cells. An update. Int J Biochem Cell Biol. 1996;28:843–61.
Soda K. The mechanisms by which polyamines accelerate tumor spread. J Exp Clin Cancer Res. 2011;30:95.
Basuroy UK, Gerner EW. Emerging concepts in targeting the polyamine metabolic pathway in epithelial cancer chemoprevention and chemotherapy. J Biochem. 2006;139:27–33.
Casero RA Jr, Marton LJ. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov. 2007;6:373–90.
Gerner EW, Meyskens FL Jr. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004;4:781–92.
Marton LJ, Pegg AE. Polyamines as targets for therapeutic intervention. Annu Rev Pharmacol Toxicol. 1995;35:55–91.
Larque E, Sabater-Molina M, Zamora S. Biological significance of dietary polyamines. Nutrition. 2007;23:87–95.
Pegg AE. Mammalian polyamine metabolism and function. IUBMB Life. 2009;61:880–94.
Urdiales JL, Medina MA, Sanchez-Jimenez F. Polyamine metabolism revisited. Eur J Gastroenterol Hepatol. 2001;13:1015–9.
Casas Ferreira AM, Moreno Cordero B, Crisolino Pozas AP, Perez Pavon JL. Use of microextraction by packed sorbents and gas chromatography-mass spectrometry for the determination of polyamines and related compounds in urine. J Chromatogr A. 2016;1444:32–41.
Xu L, You X, Cao Q, Huang M, Hong LL, Chen XL, et al. Polyamine synthesis enzyme AMD1 is closely associated with tumorigenesis and prognosis of human gastric cancers. Carcinogenesis. 2020;41:214–22.
Kabbarah O, Pinto K, Mutch DG, Goodfellow PJ. Expression profiling of mouse endometrial cancers microdissected from ethanol-fixed, paraffin-embedded tissues. Am J Pathol. 2003;162:755–62.
Scuoppo C, Miething C, Lindqvist L, Reyes J, Ruse C, Appelmann I, et al. A tumour suppressor network relying on the polyamine-hypusine axis. Nature. 2012;487:244–8.
Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, et al. Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene. 2002;21:8749–58.
Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature. 2010;466:765–8.
Park SM, Deering RP, Lu Y, Tivnan P, Lianoglou S, Al-Shahrour F, et al. Musashi-2 controls cell fate, lineage bias, and TGF-beta signaling in HSCs. J Exp Med. 2014;211:71–87.
Kwon HY, Bajaj J, Ito T, Blevins A, Konuma T, Weeks J, et al. Tetraspanin 3 is required for the development and propagation of acute myelogenous leukemia. Cell Stem Cell. 2015;17:152–64.
Vu LP, Prieto C, Amin EM, Chhangawala S, Krivtsov A, Calvo-Vidal MN, et al. Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nat Genet. 2017;49:866–75.
Imai T, Tokunaga A, Yoshida T, Hashimoto M, Mikoshiba K, Weinmaster G, et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol Cell Biol. 2001;21:3888–900.
Battelli C, Nikopoulos GN, Mitchell JG, Verdi JM. The RNA-binding protein Musashi-1 regulates neural development through the translational repression of p21WAF-1. Mol Cell Neurosci. 2006;31:85–96.
de Sousa Abreu R, Sanchez-Diaz PC, Vogel C, Burns SC, Ko D, Burton TL, et al. Genomic analyses of musashi1 downstream targets show a strong association with cancer-related processes. J Biol Chem. 2009;284:12125–35.
Das KC, Misra HP. Hydroxyl radical scavenging and singlet oxygen quenching properties of polyamines. Mol Cell Biochem. 2004;262:127–33.
Murray Stewart T, Dunston TT, Woster PM, Casero RA Jr. Polyamine catabolism and oxidative damage. J Biol Chem. 2018;293:18736–45.
Muscari C, Guarnieri C, Stefanelli C, Giaccari A, Caldarera CM. Protective effect of spermine on DNA exposed to oxidative stress. Mol Cell Biochem. 1995;144:125–9.
Rider JE, Hacker A, Mackintosh CA, Pegg AE, Woster PM, Casero RA Jr. Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide. Amino Acids. 2007;33:231–40.
Ji AR, Ku SY, Cho MS, Kim YY, Kim YJ, Oh SK, et al. Reactive oxygen species enhance differentiation of human embryonic stem cells into mesendodermal lineage. Exp Mol Med. 2010;42:175–86.
Luo M, Shang L, Brooks MD, Jiagge E, Zhu Y, Buschhaus JM, et al. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab. 2018;28:69–86 e66.
Sohal RS, Allen RG, Nations C. Oxygen free radicals play a role in cellular differentiation: an hypothesis. J Free Radic Biol Med. 1986;2:175–81.
McStay GP, Clarke SJ, Halestrap AP. Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J. 2002;367:541–8.
Sava IG, Battaglia V, Rossi CA, Salvi M, Toninello A. Free radical scavenging action of the natural polyamine spermine in rat liver mitochondria. Free Radic Biol Med. 2006;41:1272–81.
Agostinelli E, Tempera G, Molinari A, Salvi M, Battaglia V, Toninello A, et al. The physiological role of biogenic amines redox reactions in mitochondria. New perspectives in cancer therapy. Amino Acids. 2007;33:175–87.
Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103:2794–9.
Liao C, Wang Y, Tan X, Sun L, Liu S. Discovery of novel inhibitors of human S-adenosylmethionine decarboxylase based on in silico high-throughput screening and a non-radioactive enzymatic assay. Sci Rep. 2015;5:10754.
Dela Vega AL, Delcour AH. Polyamines decrease Escherichia coli outer membrane permeability. J Bacteriol. 1996;178:3715–21.
Fujisawa S, Kadoma Y. Kinetic evaluation of polyamines as radical scavengers. Anticancer Res. 2005;25:965–9.
Jung IL, Kim IG. Transcription of ahpC, katG, and katE genes in Escherichia coli is regulated by polyamines: polyamine-deficient mutant sensitive to H2O2-induced oxidative damage. Biochem Biophys Res Commun. 2003;301:915–22.
Sagor GH, Berberich T, Takahashi Y, Niitsu M, Kusano T. The polyamine spermine protects Arabidopsis from heat stress-induced damage by increasing expression of heat shock-related genes. Transgenic Res. 2013;22:595–605.
Tiburcio AF, Besford RT, Borrell A. Posttranslational regulation of arginine decarboxylase synthesis by spermine in osmotically-stressed oat leaves. Biochem Soc Trans. 1994;22:455S.
Tkachenko AG, Nesterova LY. Polyamines as modulators of gene expression under oxidative stress in Escherichia coli. Biochemistry. 2003;68:850–6.
Paridaens R, Uges DR, Barbet N, Choi L, Seeghers M, van der Graaf WT, et al. A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours. Br J Cancer. 2000;83:594–601.
Siu LL, Rowinsky EK, Hammond LA, Weiss GR, Hidalgo M, Clark GM, et al. A phase I and pharmacokinetic study of SAM486A, a novel polyamine biosynthesis inhibitor, administered on a daily-times-five every-three-week schedule in patients with advanced solid malignancies. Clin Cancer Res. 2002;8:2157–66.
Pless M, Belhadj K, Menssen HD, Kern W, Coiffier B, Wolf J, et al. Clinical efficacy, tolerability, and safety of SAM486A, a novel polyamine biosynthesis inhibitor, in patients with relapsed or refractory non-Hodgkin’s lymphoma: results from a phase II multicenter study. Clin Cancer Res. 2004;10:1299–305.
van Zuylen L, Bridgewater J, Sparreboom A, Eskens FA, de Bruijn P, Sklenar I, et al. Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer. Clin Cancer Res. 2004;10:1949–55.
Millward MJ, Joshua A, Kefford R, Aamdal S, Thomson D, Hersey P, et al. Multi-centre Phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma. Investig New Drugs. 2005;23:253–6.
Simon MS, Eckenrode J, Natale RB. Phase II trial of methylglyoxal bis-guanylhydrazone (MGBG) in refractory small cell lung cancer. Investig New Drugs. 1990;8:S79–81.
Russell DH. Increased polyamine concentrations in the urine of human cancer patients. Nat New Biol. 1971;233:144–5.
Pegg AE, McCann PP. Polyamine metabolism and function. Am J Physiol. 1982;243:C212–221.
Kim JS, Lee J, Chung HW, Choi H, Paik SG, Kim IG. Methylglyoxal-bis(guanylhydrazone), a polyamine analogue, sensitized gamma-radiation-induced cell death in HL-60 leukemia cells Sensitizing effect of MGBG on gamma-radiation-induced cell death. Environ Toxicol Pharmacol. 2006;22:160–6.
Walker JA, Miller AD, Burdo TH, McGrath MS, Williams KC. Direct targeting of macrophages with methylglyoxal-bis-guanylhydrazone decreases SIV-associated cardiovascular inflammation and pathology. J Acquir Immune Defic Syndr. 2017;74:583–92.
Gamble LD, Hogarty MD, Liu X, Ziegler DS, Marshall G, Norris MD, et al. Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma. Front Oncol. 2012;2:162.
Zimdahl B, Ito T, Blevins A, Bajaj J, Konuma T, Weeks J, et al. Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nat Genet. 2014;46:245–52.
We would also like to thank Warren Pear for the BCR-ABL construct, Gary Gilliland for the NUP98-HOXA9 construct, and Sen Liu for the personal communication regarding AO476.
This work was supported by the National Research Foundation of Korea (NRF-2020R1A2C1003791 and NRF-2019R1A5A8083404), the grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHID), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C1647) and Global Research Development Center (NRF-2016K1A4A3914725).
Conflict of interest
The authors declare that they have no conflict of interest.
All protocols for this study were reviewed and approved by Institutional Review Board.
The content of this manuscript has not been previously published and is not under consideration for publication elsewhere.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sari, I.N., Yang, YG., Wijaya, Y.T. et al. AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth. Oncogene 40, 603–617 (2021). https://doi.org/10.1038/s41388-020-01547-x