Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.CAS PubMed PubMed Central Google Scholar Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20:25–39.CAS PubMed Google Scholar Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49.CAS PubMed Google Scholar Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207–12.CAS PubMed PubMed Central Google Scholar Logtenberg MEW, Scheeren FA, Schumacher TN. The CD47-SIRPalpha immune checkpoint. Immunity. 2020;52:742–52.CAS PubMed PubMed Central Google Scholar Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184:5309–37.CAS PubMed PubMed Central Google Scholar Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352:227–31.CAS PubMed PubMed Central Google Scholar Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD. Epigenetic therapy in immune-oncology. Nat Rev Cancer. 2019;19:151–61.CAS PubMed Google Scholar Liang Y, Qu X, Shah NM, Wang T. Towards targeting transposable elements for cancer therapy. Nat Rev Cancer. 2024;24:123–40.CAS PubMed Google Scholar Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA, including endogenous retroviruses. Cell. 2015;162:974–86.CAS PubMed PubMed Central Google Scholar Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162:961–73.CAS PubMed PubMed Central Google Scholar Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, et al. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature. 2021;595:309–14.CAS PubMed PubMed Central Google Scholar Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174:549–563 e519.CAS PubMed PubMed Central Google Scholar Zhang SM, Cai WL, Liu X, Thakral D, Luo J, Chan LH, et al. KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements. Nature. 2021;598:682–7.PubMed PubMed Central Google Scholar Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma AM, et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018;359:770–5.CAS PubMed PubMed Central Google Scholar Maxwell MB, Hom-Tedla MS, Yi J, Li S, Rivera SA, Yu J, et al. ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity. Cell. 2024;187:3390–3408 e3319.CAS PubMed PubMed Central Google Scholar Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol. 2002;12:1052–8.CAS PubMed Google Scholar Lacoste N, Utley RT, Hunter JM, Poirier GG, Cote J. Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase. J Biol Chem. 2002;277:30421–4.CAS PubMed Google Scholar Shi J, Wang E, Milazzo JP, Wang Z, Kinney JB, Vakoc CR. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains. Nat Biotechnol. 2015;33:661–7.CAS PubMed PubMed Central Google Scholar Li W, Xu H, Xiao T, Cong L, Love MI, Zhang F, et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014;15:554.PubMed PubMed Central Google Scholar Miyamoto R, Yokoyama A. Protocol for fractionation-assisted native ChIP (fanChIP) to capture protein-protein/DNA interactions on chromatin. STAR Protoc. 2021;2:100404.CAS PubMed PubMed Central Google Scholar Kim D, Paggi JM, Park C, Bennett C, Salzberg SL. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019;37:907–15.CAS PubMed PubMed Central Google Scholar Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.PubMed Google Scholar Liao Y, Smyth GK, Shi W. featureCounts: an efficient general-purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.CAS PubMed Google Scholar Jin Y, Tam OH, Paniagua E, Hammell M. TEtranscripts: a package for including transposable elements in differential expression analysis of RNA-seq datasets. Bioinformatics. 2015;31:3593–9.CAS PubMed PubMed Central Google Scholar Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38:576–89.CAS PubMed PubMed Central Google Scholar Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.PubMed Central Google Scholar Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022;50:W216–W221.CAS PubMed PubMed Central Google Scholar Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation. 2021;2:100141.CAS PubMed PubMed Central Google Scholar Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.CAS PubMed PubMed Central Google Scholar Ramirez F, Ryan DP, Gruning B, Bhardwaj V, Kilpert F, Richter AS, et al. deepTools2: a next-generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016;44:W160–165.CAS PubMed PubMed Central Google Scholar Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.PubMed PubMed Central Google Scholar Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–2.CAS PubMed PubMed Central Google Scholar García-Díaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodríguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19:1189–201.PubMed PubMed Central Google Scholar Ye ZH, Jiang XM, Huang MY, Xu YL, Chen YC, Yuan LW, et al. Regulation of CD47 expression by interferon-gamma in cancer cells. Transl Oncol. 2021;14:101162.CAS PubMed PubMed Central Google Scholar Morel KL, Sheahan AV, Burkhart DL, Baca SC, Boufaied N, Liu Y, et al. EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nat Cancer. 2021;2:444–56.CAS PubMed PubMed Central Google Scholar Su P, Liu Y, Chen T, Xue Y, Zeng Y, Zhu G, et al. In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions. Nat Genet. 2024;56:1890–902.CAS PubMed PubMed Central Google Scholar Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122:1017–25.CAS PubMed PubMed Central Google Scholar Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, et al. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol Cell Biol. 2008;28:2825–39.CAS PubMed PubMed Central Google Scholar Kim SK, Jung I, Lee H, Kang K, Kim M, Jeong K, et al. Human histone H3K79 methyltransferase DOT1L protein [corrected] binds actively transcribing RNA polymerase II to regulate gene expression. J Biol Chem. 2012;287:39698–709.CAS PubMed PubMed Central Google Scholar Zhao X, Li X, Sun H, Zhao X, Gao T, Shi P, et al. Dot1l cooperates with Npm1 to repress endogenous retrovirus MERVL in embryonic stem cells. Nucleic Acids Res. 2023;51:8970–86.PubMed PubMed Central Google Scholar Coulee M, de la Iglesia A, Blanco M, Gobe C, Lapoujade C, Ialy-Radio C, et al. Chromatin environment-dependent effects of DOT1L on gene expression in male germ cells. Commun Biol. 2025;8:138.CAS PubMed PubMed Central Google Scholar Li S, Wan C, Zheng R, Fan J, Dong X, Meyer CA, et al. Cistrome-GO: a web server for functional enrichment analysis of transcription factor ChIP-seq peaks. Nucleic Acids Res. 2019;47:W206–W211.CAS PubMed PubMed Central Google Scholar Lin J, Wu Y, Tian G, Yu D, Yang E, Lam WH, et al. Menin “reads” H3K79me2 mark in a nucleosomal context. Science. 2023;379:717–23.CAS PubMed Google Scholar Sparbier CE, Gillespie A, Gomez J, Kumari N, Motazedian A, Chan KL, et al. Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes. Nat Cell Biol. 2023;25:258–72.CAS PubMed PubMed Central Google Scholar Worden EJ, Wolberger C. Activation and regulation of H2B-Ubiquitin-dependent histone methyltransferases. Curr Opin Struct Biol. 2019;59:98–106.CAS PubMed PubMed Central Google Scholar Fu R, Li Y, Jiang N, Ren BX, Zang CZ, Liu LJ, et al. Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies. J Clin Investig. 2020;130:1252–70.CAS PubMed PubMed Central Google Scholar Plaschka M, Benboubker V, Grimont M, Berthet J, Tonon L, Lopez J, et al. ZEB1 transcription factor promotes immune escape in melanoma. J Immunother Cancer. 2022;10:e003484.PubMed PubMed Central Google Scholar Zheng R, Wan C, Mei S, Qin Q, Wu Q, Sun H, et al. Cistrome Data Browser: expanded datasets and new tools for gene regulatory analysis. Nucleic Acids Res. 2019;47:D729–D735.CAS PubMed PubMed Central Google Scholar Chava S, Bugide S, Edwards YJK, Gupta R. Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis. Oncogenesis. 2021;10:48.CAS PubMed PubMed Central Google Scholar Wu A, Zhi J, Tian T, Cihan A, Cevher MA, Liu Z, et al. DOT1L complex regulates transcriptional initiation in human erythroleukemic cells. Proc Natl Acad Sci USA. 2021;118:e2106148118.CAS PubMed PubMed Central Google Scholar Kurani H, Razavipour SF, Harikumar KB, Dunworth M, Ewald AJ, Nasir A, et al. DOT1L is a novel cancer stem cell target for triple-negative breast cancer. Clin Cancer Res. 2022;28:1948–65.CAS PubMed PubMed Central Google Scholar Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165:35–44.CAS PubMed PubMed Central Google Scholar Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell. 2017;171:934–949 e916.CAS PubMed PubMed Central Google Scholar Ng HH, Feng Q, Wang H, Erdjument-Bromage H, Tempst P, Zhang Y, et al. Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev. 2002;16:1518–27.CAS PubMed PubMed Central Google Scholar Jones B, Su H, Bhat A, Lei H, Bajko J, Hevi S, et al. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS Genet. 2008;4:e1000190.PubMed PubMed Central Google Scholar Esse R, Gushchanskaia ES, Lord A, Grishok A. DOT1L complex suppresses transcription from enhancer elements and ectopic RNAi in Caenorhabditis elegans. RNA. 2019;25:1259–73.CAS PubMed PubMed Central Google Scholar Cao K, Ugarenko M, Ozark PA, Wang J, Marshall SA, Rendleman EJ, et al. DOT1L-controlled cell-fate determination and transcription elongation are independent of H3K79 methylation. Proc Natl Acad Sci USA. 2020;117:27365–73.CAS PubMed PubMed Central Google Scholar Ng HH, Ciccone DN, Morshead KB, Oettinger MA, Struhl K. Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: a potential mechanism for position-effect variegation. Proc Natl Acad Sci USA. 2003;100:1820–5.CAS PubMed PubMed Central Google Scholar Schubeler D, MacAlpine DM, Scalzo D, Wirbelauer C, Kooperberg C, van Leeuwen F, et al. The histone modification pattern of active genes was revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 2004;18:1263–71.PubMed PubMed Central Google Scholar Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature. 2013;500:598–602.CAS PubMed PubMed Central Google Scholar Tang H, Lu YF, Zeng R, Liu C, Shu Y, Wu Y, et al. DOT1L-mediated RAP80 methylation promotes BRCA1 recruitment to elicit DNA repair. Proc Natl Acad Sci USA. 2024;121:e2320804121.CAS PubMed PubMed Central Google Scholar Chen R, Ishak CA, De Carvalho DD. Endogenous retroelements and the viral mimicry response in cancer therapy and cellular homeostasis. Cancer Discov. 2021;11:2707–25.CAS PubMed Google Scholar Deblois G, Tonekaboni SAM, Grillo G, Martinez C, Kao YI, Tai F, et al. Epigenetic switch-induced viral mimicry evasion in chemotherapy-resistant breast cancer. Cancer Discov. 2020;10:1312–29.CAS PubMed Google Scholar Denas O, Sandstrom R, Cheng Y, Beal K, Herrero J, Hardison RC, et al. Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution. BMC Genomics. 2015;16:87.PubMed PubMed Central Google Scholar Monaco G, van Dam S, Casal Novo Ribeiro JL, Larbi A, de Magalhães JP. A comparison of human and mouse gene co-expression networks reveals conservation and divergence at the tissue, pathway and disease levels. BMC Evol Biol. 2015;15:259.PubMed PubMed Central Google Scholar Lin S, Lin Y, Nery JR, Urich MA, Breschi A, Davis CA, et al. Comparison of the transcriptional landscapes between human and mouse tissues. Proc Natl Acad Sci USA. 2014;111:17224–9.CAS PubMed PubMed Central Google Scholar Download references