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Dual function of DOT1L suppresses tumor intrinsic immunogenicity in Hepatocellular carcinoma [ATAC-seq]

GSE294354 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2026/04/16 Platform GPL24676
Summary
Checkpoint inhibitor therapy for Hepatocellular carcinoma (HCC) remains limited in patients’ overall response rate. Discovery and development of more effective combinatorial approaches in HCC checkpoint immunotherapy is urgent. Here, through CPlSPR/Cas9 genetic screens, we identify DOT1L as a versatile epigenetic factor that functions to suppress anti-tumor immunity through a dual mechanism. Depletion of DOT1L induces the expression of transposable elements and subsequent type-I interferon response, and meanwhile lowers ZEB1 levels to further unleash the expression of interferon simulated genes. In turn, we demonstrate that DOT1L loss or treatment with the selective DOT1L inhibitor EPZ-5676 sensitizes tumors to immune checkpoint blockade by increased immune infiltration in mouse. More importantly, EPZ-5676 treatment alone is sufficient to enhance antitumor immunity in humanized mouse model. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance.
Published in
Dual function of DOT1L suppresses tumor cell-intrinsic immunogenicity in hepatocellular carcinoma
Xu S, Gong R, Liu S et al. · Oncogene 2026 · PMID 41912776 · doi:10.1038/s41388-026-03744-6
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Direct links to NCBI, no account and no request form: the whole study as GSE294354_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 4 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1249078 and SRA study SRP578080. Searching any of these in the dataset finder brings you back here.

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