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We performed targeted exome sequencing on 90 patients with SCLC, including two with c\u2010SCLC, and discovered <jats:italic>RUNX1T1<\/jats:italic> amplification specific to small cell tumors of both patients with c\u2010SCLC, but in only 2 of 88 \u2018pure\u2019 SCLC patients. <jats:italic>RUNX1T1<\/jats:italic> was first identified in the fusion transcript AML1\/ETO, which occurs in 12%\u201015% of acute myelogenous leukemia (AML). We further show higher expression of <jats:italic>RUNX1T1<\/jats:italic> in the SCLC component of another c\u2010SCLC tumor by <jats:italic>in situ<\/jats:italic> hybridization. <jats:italic>RUNX1T1<\/jats:italic> expression was enriched in SCLC compared with all other cancers, including NSCLC, in both cell lines and tumor specimens, as shown by mRNA level and western blotting. Transcriptomic analysis of hallmark genes decreased by stable <jats:italic>RUNX1T1<\/jats:italic> overexpression revealed a significant change in E2F targets. Validation experiments in multiple lung cancer cell lines showed that <jats:italic>RUNX1T1<\/jats:italic> overexpression consistently decreased <jats:italic>CDKN1A<\/jats:italic> (p21) expression and increased E2F transcriptional activity, which is commonly altered in SCLC. Chromatin immunoprecipitation (ChIP) in these overexpressing cells demonstrated that RUNX1T1 interacts with the <jats:italic>CDKN1A<\/jats:italic> (p21) promoter region, which displayed parallel reductions in histone 3 acetylation. Furthermore, reduced p21 expression could be dramatically restored by HDAC inhibition using Trichostatin A. Reanalysis of ChIP\u2010seq data in Kasumi\u20101 AML cells showed that knockdown of the RUNX1T1 fusion protein was associated with increased global acetylation, including the CDKN1A (p21) promoter. Thus, our study identifies <jats:italic>RUNX1T1<\/jats:italic> as a biomarker and potential epigenetic regulator of SCLC.<\/jats:p>","DOI":"10.1002\/1878-0261.12829","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T06:52:39Z","timestamp":1603263159000},"page":"195-209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Identification of RUNX1T1 as a potential epigenetic modifier in small\u2010cell lung cancer"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1070-121X","authenticated-orcid":false,"given":"Tian","family":"He","sequence":"first","affiliation":[{"name":"Department of Biochemistry School of Medicine Case Western Reserve University Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Wildey","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology Case Western 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