{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:54:45Z","timestamp":1790708085903,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T00:00:00Z","timestamp":1571961600000},"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>Leukemias bearing mixed lineage leukemia (MLL) rearrangement (MLL-R) resulting in expression of oncogenic MLL fusion proteins (MLL-FPs) represent an especially aggressive disease subtype with the worst overall prognoses and chemotherapeutic response. MLL-R leukemias are uniquely dependent on the epigenetic function of the H3K79 methyltransferase DOT1L, which is misdirected by MLL-FPs activating gene expression, driving transformation and leukemogenesis. Given the functional necessity of these leukemias to maintain adequate methylation potential allowing aberrant activating histone methylation to proceed, driving leukemic gene expression, we investigated perturbation of methionine (Met)\/S-adenosylmethionine (SAM) metabolism as a novel therapeutic paradigm for MLL-R leukemia. Disruption of Met\/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells. Global histone methylation dynamics were altered, with a profound loss of requisite H3K79 methylation, indicating inhibition of DOT1L function. Relative occupancy of the repressive H3K27me3 modification was increased at the DOT1L promoter in MLL-R cells, and DOT1L mRNA and protein expression was reduced. Finally, pharmacologic inhibition of Met\/SAM metabolism significantly prolonged survival in an advanced, clinically relevant patient\u2013derived MLL-R leukemia xenograft model, in combination with cytotoxic induction chemotherapy. Our findings provide support for further investigation into the development of highly specific allosteric inhibitors of enzymatic mediators of Met\/SAM metabolism or dietary manipulation of methionine levels. Such inhibitors may lead to enhanced treatment outcomes for MLL-R leukemia, along with cytotoxic chemotherapy or DOT1L inhibitors.<\/jats:p>","DOI":"10.3390\/cells8111322","type":"journal-article","created":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T11:05:18Z","timestamp":1572001518000},"page":"1322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Perturbation of Methionine\/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-2236","authenticated-orcid":false,"given":"Aditya","family":"Barve","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9359-6880","authenticated-orcid":false,"given":"Alexis","family":"Vega","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parag P.","family":"Shah","sequence":"additional","affiliation":[{"name":"James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita","family":"Ghare","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavona","family":"Casson","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Wunderlich","sequence":"additional","affiliation":[{"name":"Department of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah J.","family":"Siskind","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi J.","family":"Beverly","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fped.2017.00004","article-title":"MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches","volume":"5","author":"Winters","year":"2017","journal-title":"Front. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1182\/blood.V96.1.24","article-title":"Biological and therapeutic aspects of infant leukemia","volume":"96","author":"Biondi","year":"2000","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1182\/asheducation-2011.1.354","article-title":"Targeting epigenetic programs in MLL-rearranged leukemias","volume":"2011","author":"Bernt","year":"2011","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nrc2253","article-title":"MLL translocations, histone modifications and leukaemia stem-cell development","volume":"7","author":"Krivtsov","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.cell.2005.02.020","article-title":"hDOT1L links histone methylation to leukemogenesis","volume":"121","author":"Okada","year":"2005","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/ncb1464","article-title":"Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L","volume":"8","author":"Okada","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/leu.2012.327","article-title":"Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l","volume":"27","author":"Chen","year":"2013","journal-title":"Leukemia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ccr.2011.06.009","article-title":"Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor","volume":"20","author":"Daigle","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1182\/blood-2013-04-497644","article-title":"Potent inhibition of DOT1L as treatment of MLL-fusion leukemia","volume":"122","author":"Daigle","year":"2013","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1182\/blood-2012-11-465120","article-title":"Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l","volume":"121","author":"Deshpande","year":"2013","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6912","DOI":"10.1182\/blood-2011-02-334359","article-title":"DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis","volume":"117","author":"Nguyen","year":"2011","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1182\/blood-2017-12-818948","article-title":"The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia","volume":"131","author":"Stein","year":"2018","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3389\/fonc.2018.00041","article-title":"Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia","volume":"8","author":"Sun","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/cr.2011.22","article-title":"Regulation of chromatin by histone modifications","volume":"21","author":"Bannister","year":"2011","journal-title":"Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0163-7258(96)00197-0","article-title":"S-adenosylmethionine synthesis: Molecular mechanisms and clinical implications","volume":"73","author":"Mato","year":"1997","journal-title":"Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1151S","DOI":"10.1093\/ajcn\/76.5.1151S","article-title":"S-Adenosyl-L-methionine (SAMe): From the bench to the bedside--molecular basis of a pleiotrophic molecule","volume":"76","author":"Bottiglieri","year":"2002","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0021-9258(18)66148-4","article-title":"S-Adenosylmethionine; a new intermediate formed enzymatically from L-methionine and adenosinetriphosphate","volume":"204","author":"Catoni","year":"1953","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1096\/fasebj.4.5.2407589","article-title":"Cobalamin-dependent methionine synthase","volume":"4","author":"Banerjee","year":"1990","journal-title":"Faseb J"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.3945\/ajcn.112.048462","article-title":"DNA methylation potential: Dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women","volume":"97","author":"Moore","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/cr.2008.314","article-title":"Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells","volume":"19","author":"Jani","year":"2009","journal-title":"Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1038\/s41598-019-40519-4","article-title":"Primary lung cancer samples cultured under microenvironment-mimetic conditions enrich for mesenchymal stem-like cells that promote metastasis","volume":"9","author":"Saforo","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"412","DOI":"10.4049\/jimmunol.1400055","article-title":"Coordinated histone H3 methylation and acetylation regulate physiologic and pathologic fas ligand gene expression in human CD4+ T cells","volume":"193","author":"Ghare","year":"2014","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/sj.leu.2403222","article-title":"NOD\/SCID mice engineered to express human IL-3, GM-CSF and Steel factor constitutively mobilize engrafted human progenitors and compromise human stem cell regeneration","volume":"18","author":"Nicolini","year":"2004","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.exphem.2018.08.004","article-title":"Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis, leukemogenesis, and therapeutic response","volume":"67","author":"Barve","year":"2018","journal-title":"Exp. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41467-018-08011-1","article-title":"Promotion of homology-directed DNA repair by polyamines","volume":"10","author":"Lee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1080\/09553008914550821","article-title":"Inhibition of X-ray-induced DNA strand break repair in polyamine-depleted HeLa cells","volume":"55","author":"Snyder","year":"1989","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/j.1751-1097.1990.tb01795.x","article-title":"Effect of polyamine depletion on DNA damage and repair following UV irradiation of HeLa cells","volume":"52","author":"Snyder","year":"1990","journal-title":"Photochem. Photobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.celrep.2016.03.043","article-title":"MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A\/PRMT5\/RIOK1 Axis","volume":"15","author":"Marjon","year":"2016","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.ctrv.2012.01.004","article-title":"A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension","volume":"38","author":"Cavuoto","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.molcel.2012.02.016","article-title":"Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-kappaB target genes","volume":"46","author":"Erener","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S1357-2725(03)00215-2","article-title":"Caspase-dependent apoptosis and -independent poly(ADP-ribose) polymerase cleavage induced by transforming growth factor beta1","volume":"36","author":"Yang","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1478-811X-8-31","article-title":"PARP-1 cleavage fragments: Signatures of cell-death proteases in neurodegeneration","volume":"8","author":"Chaitanya","year":"2010","journal-title":"Cell Commun Signal"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1148S","DOI":"10.1093\/ajcn\/76.5.1148S","article-title":"S-Adenosylmethionine: Molecular, biological, and clinical aspects--an introduction","volume":"76","author":"Lieber","year":"2002","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1007\/s00726-014-1765-4","article-title":"Regulation of autophagy by amino acids and MTOR-dependent signal transduction","volume":"47","author":"Meijer","year":"2015","journal-title":"Amino Acids"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1101\/gad.283416.116","article-title":"Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells","volume":"30","author":"Guo","year":"2016","journal-title":"Genes Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.cell.2013.06.041","article-title":"Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A","volume":"154","author":"Sutter","year":"2013","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/cbic.201000545","article-title":"Structure and function of histone H3 lysine 9 methyltransferases and demethylases","volume":"12","author":"Krishnan","year":"2011","journal-title":"Chembiochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1089\/adt.2012.480","article-title":"Assay development for histone methyltransferases","volume":"11","author":"Horiuchi","year":"2013","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1089\/adt.2014.609","article-title":"Biochemical Assay Development for Histone Methyltransferases Using a Transcreener-Based Assay for S-Adenosylhomocysteine","volume":"13","author":"Kumar","year":"2015","journal-title":"Assay Drug Dev. Technol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/11\/1322\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:29:29Z","timestamp":1760189369000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/11\/1322"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,25]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["cells8111322"],"URL":"https:\/\/doi.org\/10.3390\/cells8111322","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,25]]}}}