Abstract
Acute myeloid leukemia (AML) is considered a poor prognosis malignancy where patients exhibit altered glucose metabolism and stem cell signatures that contribute to AML growth and maintenance. Here, we report that the epigenetic factor, Ten-Eleven Translocation 3 (TET3) dioxygenase is overexpressed in AML patients and functionally validated human leukemic stem cells (LSCs), is required for leukemic growth by virtue of its regulation of glucose metabolism in AML cells. In human AML cells, TET3 maintains 5-hydroxymethylcytosine (5hmC) epigenetic marks and expression of early myeloid progenitor program, critical glucose metabolism and STAT5A signaling pathway genes, which also positively correlate with TET3 expression in AML patients. Consequently, TET3 depletion impedes hexokinase activity and L-Lactate production in AML cells. Conversely, overexpression of TET3 in healthy human hematopoietic stem progenitors (HSPCs) upregulates the expression of glucose metabolism, STAT5A signaling and AML associated genes, and impairs normal HSPC lineage differentiation in vitro. Finally, TET3 depletion renders AML cells highly sensitive to blockage of the TET3 downstream pathways glycolysis and STAT5 signaling via the combination of 2-Deoxy-D-glucose and STAT5 inhibitor which preferentially targets AML cells but spares healthy CD34+ HSPCs.
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References
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30.
Chen WL, Wang JH, Zhao AH, Xu X, Wang YH, Chen TL, et al. A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value. Blood. 2014;124:1645–54.
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.
Jones CL, Stevens BM, D’Alessandro A, Reisz JA, Culp-Hill R, Nemkov T, et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. 2018;34:724–40.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.
Huang H, Jiang X, Li Z, Li Y, Song CX, He C, et al. TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc Natl Acad Sci USA. 2013;110:11994–9.
An J, Gonzalez-Avalos E, Chawla A, Jeong M, Lopez-Moyado IF, Li W, et al. Acute loss of TET function results in aggressive myeloid cancer in mice. Nat Commun. 2015;6:10071.
Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017;170:1079–95.
Yan H, Wang Y, Qu X, Li J, Hale J, Huang Y, et al. Distinct roles for TET family proteins in regulating human erythropoiesis. Blood. 2017;129:2002–12.
Xue S, Liu C, Sun X, Li W, Zhang C, Zhou X, et al. TET3 inhibits type I IFN production independent of DNA demethylation. Cell Rep. 2016;16:1096–105.
Kroeze LI, Aslanyan MG, van Rooij A, Koorenhof-Scheele TN, Massop M, Carell T, et al. Characterization of acute myeloid leukemia based on levels of global hydroxymethylation. Blood. 2014;124:1110–8.
Wu MZ, Chen SF, Nieh S, Benner C, Ger LP, Jan CI, et al. Hypoxia drives breast tumor malignancy through a TET-TNFalpha-p38-MAPK signaling axis. Cancer Res. 2015;75:3912–24.
Bhattacharyya S, Pradhan K, Campbell N, Mazdo J, Vasantkumar A, Maqbool S, et al. Altered hydroxymethylation is seen at regulatory regions in pancreatic cancer and regulates oncogenic pathways. Genome Res. 2017;27:1830–42.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
Rawat VPS, Götze M, Rasalkar A, Vegi NM, Ihme S, Thoene S, et al. The microRNA miR-196b acts as a tumor suppressor in Cdx2-driven acute myeloid leukemia. Haematologica. 2020;105:e285–9.
Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, et al. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell. 2015;57:662–73.
Morinishi L, Kochanowski K, Levine RL, Wu LF, Altschuler SJ. Loss of TET2 affects proliferation and drug sensitivity through altered dynamics of cell-state transitions. Cell Syst. 2020;11:86–94.
Jiang X, Hu C, Ferchen K, Nie J, Cui X, Chen CH, et al. Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun. 2017;8:2099.
Deplus R, Delatte B, Schwinn MK, Defrance M, Mendez J, Murphy N, et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 2013;32:645–55.
Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J, et al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep. 2014;9:1841–55.
Muller J, Sperl B, Reindl W, Kiessling A, Berg T. Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem. 2008;9:723–7.
Darvin P, Sasidharan Nair V, Elkord E. PD-L1 expression in human breast cancer stem cells is epigenetically regulated through posttranslational histone modifications. J Oncol. 2019;2019:3958908.
Xu F, Liu Z, Liu R, Lu C, Wang L, Mao W, et al. Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma. Cell Commun Signal. 2020;18:17.
Perera A, Eisen D, Wagner M, Laube SK, Kunzel AF, Koch S, et al. TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression. Cell Rep. 2015;11:283–94.
Yue X, Lio CJ, Samaniego-Castruita D, Li X, Rao A. Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nat Commun. 2019;10:2011.
Shrestha R, Sakata-Yanagimoto M, Maie K, Oshima M, Ishihara M, Suehara Y, et al. Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status. Blood Adv. 2020;4:845–54.
Guan Y, Tiwari AD, Phillips JG, Hasipek M, Grabowski DR, Pagliuca S, et al. A therapeutic strategy for preferential targeting of TET2 mutant and TET-dioxygenase deficient cells in myeloid neoplasms. Blood Cancer Disco. 2021;2:146–61.
Venton G, Perez-Alea M, Baier C, Fournet G, Quash G, Labiad Y, et al. Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors. Blood Cancer J. 2016;6:e469.
Zhang TJ, Zhou JD, Zhang W, Lin J, Ma JC, Wen XM, et al. H19 overexpression promotes leukemogenesis and predicts unfavorable prognosis in acute myeloid leukemia. Clin Epigenetics. 2018;10:47.
Da L, Cao T, Sun X, Jin S, Di X, Huang X, et al. Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4alpha fetal isoform. Nat Commun. 2020;11:342.
Lin G, Sun W, Yang Z, Guo J, Liu H, Liang J. Hypoxia induces the expression of TET enzymes in HepG2 cells. Oncol Lett. 2017;14:6457–62.
Cao JZ, Liu H, Wickrema A, Godley LA. HIF-1 directly induces TET3 expression to enhance 5-hmC density and induce erythroid gene expression in hypoxia. Blood Adv. 2020;4:3053–62.
Polak A, Bialopiotrowicz E, Krzymieniewska B, Wozniak J, Stojak M, Cybulska M, et al. SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism. Cell Death Dis. 2020;11:956.
Wingelhofer B, Maurer B, Heyes EC, Cumaraswamy AA, Berger-Becvar A, de Araujo ED, et al. Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Leukemia. 2018;32:1135–46.
Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41.
Iwasaki M, Liedtke M, Gentles AJ, Cleary ML. CD93 marks a non-quiescent human leukemia stem cell population and is required for development of MLL-rearranged acute myeloid leukemia. Cell Stem Cell. 2015;17:412–21.
Acknowledgements
The authors would like to thank all members of the animal facility, genomics and flow cytometry core facilities of the University of Ulm, Germany. The work was supported by a grant received by VPSR from the Ministry of Science, Research and the Art (MWK), Baden-Württemberg, Germany (Junior-professor Program). CB was funded by a grant from the DFG (SFB 1074 project A4 to CB). We thank Prof. Konstanze Döhner and Prof. Hartmut Döhner (Department of Internal Medicine III, University Hospital Ulm) for providing patient samples. We thank Marc Young (Institute of Immunology, University Hospital Ulm) for his assistance with generating Fig. 1A.
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VPSR designed the project, CB discussed and edited the design of the project. AJP, SB, TA and FM performed experiments. AJP, KF and TM performed transplantations. AJP, SB, CB, and VPSR analyzed the data. SB and AJP performed the RNA-seq, ChIP-seq data analysis in collaboration with AS. UK and LQM performed histopathology. NMV contributed research material. AJP, SB, VPSR, and CB contributed to interpretation of patient data. SB, AJP, CB, and VPSR wrote the manuscript.
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Pulikkottil, A.J., Bamezai, S., Ammer, T. et al. TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways. Leukemia 36, 416–425 (2022). https://doi.org/10.1038/s41375-021-01390-3
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DOI: https://doi.org/10.1038/s41375-021-01390-3
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