{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:01:59Z","timestamp":1774274519774,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Erythroid acute myeloid leukemia (AML) cell line OCI-M2 expresses a particular oncogenic network: IRF6, in concert with ETV2 and HEY1, aberrantly activates NKL homeobox gene NKX2-4, which in turn represses megakaryocytic lineage factor FLI1. Interestingly, in keratinocytes, IRF6 is able to bind glucose which promotes IRF6-dimerization and thus alters its binding site selection. Here, we used OCI-M2 as a model to investigate the role of glucose level and IRF6 in leukemogenesis. Treatment of OCI-M2 with high glucose or 2-deoxy-glucose resulted in the downregulation of IRF6 and NKX2-4, and the upregulation of FLI1, indicating that glucose-mediated dimerization of IRF6 altered its reported autoactivation. The screening of this cell line for genes encoding glycolytic enzymes identified aberrant overexpression of glucose-6-phosphate isomerase (GPI) and phosphofructokinase L (PFKL), which were targeted by genomic amplification and chromothripsis-like alterations, respectively. Furthermore, GPI was activated by NKX2-4 and ETV2, and PFKL by ETV2. Finally, siRNA-mediated downregulation of PFKL resulted in elevated glucose levels, suppressed expression of IRF6 and NKX2-4, and activated FLI1. Thus, we connected an oncogenic regulatory network with deregulated glycolytic enzymes and glucose metabolism, thereby establishing a new in vitro model to develop novel therapeutic avenues in AML subsets.<\/jats:p>","DOI":"10.3390\/cells15060569","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glycolytic Enzymes Are Part of an Oncogenic Network in AML"],"prefix":"10.3390","volume":"15","author":[{"given":"Stefan","family":"Nagel","sequence":"first","affiliation":[{"name":"Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinna","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9448-416X","authenticated-orcid":false,"given":"Claudia","family":"Pommerenke","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","first-page":"26","article-title":"Differentiation therapy of myeloid leukemia: Four decades of development","volume":"106","author":"Madan","year":"2021","journal-title":"Haematologica"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1016\/j.neuron.2022.07.012","article-title":"Neuroblastoma: When differentiation goes awry","volume":"110","author":"Zeineldin","year":"2022","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.cell.2006.06.052","article-title":"Multilineage transcriptional priming and determination of alternate hematopoietic cell fates","volume":"126","author":"Laslo","year":"2006","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.stem.2010.07.016","article-title":"Combinatorial transcriptional control in blood stem\/progenitor cells: Genome-wide analysis of ten major transcriptional regulators","volume":"7","author":"Wilson","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.3324\/haematol.2019.216861","article-title":"To be red or white: Lineage commitment and maintenance of the hematopoietic system by the \u201cinner myeloid\u201d","volume":"104","author":"Kato","year":"2019","journal-title":"Haematologica"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3892\/mmr.2024.13231","article-title":"An intricate regulatory circuit between FLI1 and GATA1\/GATA2\/LDB1\/ERG dictates erythroid vs. megakaryocytic differentiation","volume":"29","author":"Wang","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1620\/tjem.242.83","article-title":"GATA Transcription Factors: Basic Principles and Related Human Disorders","volume":"242","author":"Fujiwara","year":"2017","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s00018-022-04160-1","article-title":"Current insights into the role of Fli-1 in hematopoiesis and malignant transformation","volume":"79","author":"Gajendran","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Nagel, S., Pommerenke, C., Meyer, C., and MacLeod, R.A.F. (2022). The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063192"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s00412-015-0543-8","article-title":"Homeodomain proteins: An update","volume":"125","author":"Affolter","year":"2016","journal-title":"Chromosoma"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Holland, P.W., Booth, H.A., and Bruford, E.A. (2007). Classification and nomenclature of all human homeobox genes. BMC Biol., 5.","DOI":"10.1186\/1741-7007-5-47"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nagel, S. (2021). NKL-Code in Normal and Aberrant Hematopoiesis. Cancers, 13.","DOI":"10.3390\/cancers13081961"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nagel, S., Pommerenke, C., Meyer, C., and MacLeod, R.A.F. (2021). NKL Homeobox Genes NKX2-3 and NKX2-4 Deregulate Megakaryocytic-Erythroid Cell Differentiation in AML. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111434"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/imm.70045","article-title":"Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies","volume":"177","author":"Ahuja","year":"2026","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1655005","DOI":"10.3389\/fimmu.2025.1655005","article-title":"Metabolic reprogramming and immune regulation in acute myeloid leukemia","volume":"16","author":"Hao","year":"2025","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.molcel.2024.12.012","article-title":"Metabolism-driven chromatin dynamics: Molecular principles and technological advances","volume":"85","author":"Sahu","year":"2025","journal-title":"Mol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.stem.2025.02.017","article-title":"Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation","volume":"32","author":"Bhaduri","year":"2025","journal-title":"Cell Stem Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1158\/0008-5472.CAN-06-2615","article-title":"Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3\u2032-BCL11B enhancers and coregulation by PU.1 and HMGA1","volume":"67","author":"Nagel","year":"2007","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8218","DOI":"10.1038\/s41598-019-44491-x","article-title":"The LL-100 panel: 100 cell lines for blood cancer studies","volume":"9","author":"Quentmeier","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"420","DOI":"10.12688\/f1000research.111175.2","article-title":"DSMZCellDive: Diving into high-throughput cell line data","volume":"11","author":"Koblitz","year":"2022","journal-title":"F1000Research"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D498","DOI":"10.1093\/nar\/gkaa1025","article-title":"BRENDA, the ELIXIR core data resource in 2021: New developments and updates","volume":"49","author":"Chang","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/leu.2015.95","article-title":"NFATc1 as a therapeutic target in FLT3-ITD-positive AML","volume":"29","author":"Metzelder","year":"2015","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network, Weinstein, J.N., Collisson, E.A., Mills, G.B., Shaw, K.R., Ozenberger, B.A., Ellrott, K., Shmulevich, I., Sander, C., and Stuart, J.M. (2013). The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet., 45, 1113\u20131120.","DOI":"10.1038\/ng.2764"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/gbe\/evy275","article-title":"Day and Night: Metabolic Profiles and Evolutionary Relationships of Six Axenic Non-Marine Cyanobacteria","volume":"11","author":"Will","year":"2019","journal-title":"Genome Biol. Evol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9568","DOI":"10.1038\/s41467-024-53634-2","article-title":"High incidence and geographic distribution of cleft palate in Finland are associated with the IRF6 gene","volume":"15","author":"Rahimov","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.leukres.2011.03.010","article-title":"Deregulated expression of Kruppel-like factors in acute myeloid leukemia","volume":"35","author":"Humbert","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1002\/cam4.2911","article-title":"Expression of human Kr\u00fcppel-like factor 3 in peripheral blood as a promising biomarker for acute leukemia","volume":"9","author":"Yan","year":"2020","journal-title":"Cancer Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1002\/gcc.22069","article-title":"Chromothripsis in Hodgkin lymphoma","volume":"52","author":"Nagel","year":"2013","journal-title":"Genes. Chromosomes Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1038\/s41588-025-02190-6","article-title":"Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A","volume":"57","author":"Brierley","year":"2025","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Campos, M., and Albrecht, L.V. (2023). Hitting the Sweet Spot: How Glucose Metabolism Is Orchestrated in Space and Time by Phosphofructokinase-1. Cancers, 16.","DOI":"10.3390\/cancers16010016"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41420-023-01707-4","article-title":"HES1 promotes aerobic glycolysis and cancer progression of colorectal cancer via IGF2BP2-mediated GLUT1 m6A modification","volume":"9","author":"Wang","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1186\/s12967-025-06897-2","article-title":"Phosphofructokinase-1 redefined: A metabolic hub orchestrating cancer hallmarks through multi-dimensional control networks","volume":"23","author":"Yuan","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6027","DOI":"10.1007\/s13277-015-4428-5","article-title":"Inhibition of pentose phosphate pathway suppresses acute myelogenous leukemia","volume":"37","author":"Chen","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e35721","DOI":"10.1016\/j.heliyon.2024.e35721","article-title":"Glycolysis and chemoresistance in acute myeloid leukemia","volume":"10","author":"Yang","year":"2024","journal-title":"Heliyon"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.3389\/fonc.2019.01143","article-title":"Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches","volume":"9","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"25742","DOI":"10.1038\/s41598-024-76919-4","article-title":"A novel risk score model of lactate metabolism for predicting outcomes and immune signatures in acute myeloid leukemia","volume":"14","author":"Huang","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1182\/bloodadvances.2020003521","article-title":"LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C\/EBP\u03b1","volume":"5","author":"Kohrogi","year":"2021","journal-title":"Blood Adv."},{"key":"ref_40","first-page":"222","article-title":"ETV2 regulating PHD2-HIF-1\u03b1 axis controls metabolism reprogramming promotes vascularized bone regeneration","volume":"37","author":"Du","year":"2024","journal-title":"Bioact. Mater."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41419-025-07932-2","article-title":"Degradation of IRF6 by TRIM59 in tumor cells triggers PGM1-mediated glycolysis to regulate cell proliferation in neuroblastoma","volume":"16","author":"Zeng","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jin, G.Z., Zhang, Y., Cong, W.M., Wu, X., Wang, X., Wu, S., Wang, S., Zhou, W., Yuan, S., and Gao, H. (2018). Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2006483"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"111713","DOI":"10.1016\/j.yexcr.2019.111713","article-title":"TWIST1 transcriptionally regulates glycolytic genes to promote the Warburg metabolism in pancreatic cancer","volume":"386","author":"Wang","year":"2020","journal-title":"Exp. Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ab\u00e1igar, M., Robledo, C., Benito, R., Ramos, F., D\u00edez-Campelo, M., Hermos\u00edn, L., S\u00e1nchez-Del-Real, J., Alonso, J.M., Cuello, R., and Megido, M. (2016). Chromothripsis Is a Recurrent Genomic Abnormality in High-Risk Myelodysplastic Syndromes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0164370"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/ajh.27575","article-title":"Chromoanagenesis Is Frequently Associated with Highly Complex Karyotypes, Extensive Clonal Heterogeneity, and Treatment Refractoriness in Acute Myeloid Leukemia","volume":"100","author":"Wei","year":"2025","journal-title":"Am. J. Hematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41576-023-00663-0","article-title":"Scrambling the genome in cancer: Causes and consequences of complex chromosome rearrangements","volume":"25","author":"Krupina","year":"2024","journal-title":"Nat. Rev. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Bartrons, R., Simon-Molas, H., Rodr\u00edguez-Garc\u00eda, A., Casta\u00f1o, E., Navarro-Sabat\u00e9, \u00c0., Manzano, A., and Martinez-Outschoorn, U.E. (2018). Fructose 2,6-Bisphosphate in Cancer Cell Metabolism. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00331"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19758","DOI":"10.1074\/jbc.M114.584540","article-title":"Interferon regulatory factor 6 differentially regulates Toll-like receptor 2-dependent chemokine gene expression in epithelial cells","volume":"289","author":"Kwa","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.devcel.2012.09.003","article-title":"Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis","volume":"23","author":"Xu","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Joly, S., Rhea, L., Volk, P., Moreland, J.G., and Dunnwald, M. (2016). Interferon Regulatory Factor 6 Has a Protective Role in the Host Response to Endotoxic Shock. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152385"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/6\/569\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:13:19Z","timestamp":1774271599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/6\/569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["cells15060569"],"URL":"https:\/\/doi.org\/10.3390\/cells15060569","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]}}}