{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:57:26Z","timestamp":1790301446250,"version":"4.1.0"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T00:00:00Z","timestamp":1530662400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T00:00:00Z","timestamp":1530662400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T00:00:00Z","timestamp":1530662400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100010318","name":"University of Manitoba","doi-asserted-by":"publisher","award":["43887"],"award-info":[{"award-number":["43887"]}],"id":[{"id":"10.13039\/100010318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010318","name":"University of Manitoba","doi-asserted-by":"publisher","award":["48819"],"award-info":[{"award-number":["48819"]}],"id":[{"id":"10.13039\/100010318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008795","name":"Manitoba Medical Services Foundation","doi-asserted-by":"publisher","award":["8-2014-03 2014"],"award-info":[{"award-number":["8-2014-03 2014"]}],"id":[{"id":"10.13039\/100008795","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008794","name":"Research Manitoba","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2015-06543"],"award-info":[{"award-number":["RGPIN-2015-06543"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dr. Paul H.T. Thorlakson Foundation Fund, University of Manitoba"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mixed lineage leukemia results from chromosomal rearrangements of the gene mixed lineage leukemia (MLL). MLL-AF9 is one such rearrangement that recruits the lysine methyltransferase, human disruptor of telomere silencing 1-like (DOT1L) and lysine specific demethylase 1 (LSD1), resulting in elevated expression of the Homeobox protein A9 (HOXA9), and leukemia. Inhibitors of LSD1 or DOT1L reduce HOXA9 expression, kill MLL-rearranged cells, and may treat leukemia. To quantify their effects on histone modifying enzyme activity and expression in MLL-rearranged leukemia, we tested inhibitors of DOT1L (EPZ-5676), LSD1 (GSK2879552), and HDAC (mocetinostat), in the MLL-AF9 cell line MOLM-13. All inhibitors reduced MOLM-13 viability but only mocetinostat induced apoptosis. EPZ-5676 increased total histone lysine dimethylation, which was attributed to a reduction in LSD1 expression, and was indistinguishable from direct LSD1 inhibition by GSK2879552. All compounds directly inhibit, or reduce the expression of, HOXA9, DOT1L and LSD1 by qPCR, increase total histone lysine methylation and acetylation by LC-MS\/MS, and specifically reduce H3K79Me2 and increase H3K14Ac. Each inhibitor altered the expression of many histone modifying enzymes which may precipitate additional changes in expression. To the extent that this decreases HOXA9 expression it benefits mixed lineage leukemia treatment, all other expression changes are off-target effects.<\/jats:p>","DOI":"10.1021\/acs.jproteome.8b00118","type":"journal-article","created":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T10:38:42Z","timestamp":1530700722000},"page":"2657-2667","source":"Crossref","is-referenced-by-count":28,"title":["Selective DOT1L,\nLSD1, and HDAC Class I Inhibitors\nReduce HOXA9 Expression in MLL-AF9 Rearranged Leukemia Cells, But\nDysregulate the Expression of Many Histone-Modifying Enzymes"],"prefix":"10.1021","volume":"17","author":[{"given":"Ryan","family":"Lillico","sequence":"first","affiliation":[{"name":"University of Manitoba , , 750 McDermot Avenue , , ,","place":["Winnipeg, Manitoba, Canada, R3E 0T5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney K.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"University of Manitoba , , 750 McDermot Avenue , , ,","place":["Winnipeg, Manitoba, Canada, R3E 0T5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6625-6717","authenticated-orcid":true,"given":"Ted M.","family":"Lakowski","sequence":"additional","affiliation":[{"name":"University of Manitoba , , 750 McDermot Avenue , , ,","place":["Winnipeg, Manitoba, Canada, R3E 0T5"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,7,4]]},"reference":[{"key":"2026081723130126400_cit1","first-page":"2823","article-title":"The histone methyltransferase DOT1L:\nregulatory functions and a cancer therapy target","volume":"5","author":"Wong","year":"2015","journal-title":"American Journal of Cancer Research"},{"key":"2026081723130126400_cit2","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1038\/leu.2014.169","article-title":"The emerging roles of DOT1L in leukemia\nand normal development","volume":"28","author":"McLean","year":"2014","journal-title":"Leukemia"},{"key":"2026081723130126400_cit3","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/S0092-8674(03)00114-4","article-title":"Structure\nof the catalytic domain of human DOT1L, a non-SET domain nucleosomal\nhistone methyltransferase","volume":"112","author":"Min","year":"2003","journal-title":"Cell"},{"key":"2026081723130126400_cit4","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1101\/gad.2057811","article-title":"The diverse functions\nof Dot1 and H3K79 methylation","volume":"25","author":"Nguyen","year":"2011","journal-title":"Genes Dev."},{"key":"2026081723130126400_cit5","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s13148-016-0223-4","article-title":"Targeting histone methyltransferases\nand demethylases in clinical trials for cancer therapy","volume":"8","author":"Morera","year":"2016","journal-title":"Clin. 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