Comprehensive characterization of VSIR reveals dual epigenetic regulation and immune landscape across hematological malignancies

VISTA (V-domain Immunoglobulin Suppressor of T cell Activation), encoded by VSIR, functions as an inhibitory checkpoint predominantly expressed on myeloid cells. Despite its recognized role in solid tumors, systematic characterization of VSIR regulation and clinical implications in hematological malignancies remains limited. We performed integrative multi-omics analyses of diverse hematological malignancies (> 10,000 transcriptomes) to elucidate VSIR expression patterns, epigenetic regulation, and therapeutic potential. VSIR exhibited preferential upregulation in hematological malignancies, particularly myeloid leukemias. We identified dual epigenetic mechanisms driving VSIR overexpression: promoter hypomethylation progressively intensified from healthy controls through myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML), validated by targeted bisulfite sequencing in 130 clinical samples; chromatin immunoprecipitation sequencing revealed direct transcriptional activation by KMT2A fusion proteins through enrichment of H3K4me3, H3K79me2, and H3K27ac activating marks at the VSIR promoter. Menin inhibitor treatment substantially reduced KMT2A occupancy and histone modifications, confirming Menin-dependent regulation. Similarly, NPM1 mutations promoted VSIR expression through stabilizing Menin-containing chromatin complexes. Functionally, VSIR-high tumors showed enrichment in immune regulatory pathways and predicted favorable immunotherapy responses. Prognostically, elevated VSIR expression conferred adverse outcomes in AML while predicting improved survival in DLBCL and MM. Computationally, VSIR-high patients showed increased likelihood of benefiting from immune checkpoint blockade, validated in real-world immunotherapy cohorts. The elucidated Menin-VSIR regulatory axis suggests potential for combining Menin inhibitors with VISTA checkpoint blockade in KMT2A-rearranged AML. Our findings suggest that VSIR expression is epigenetically dysregulated in hematological malignancies through dual mechanisms, which could inform biomarker-driven patient selection and rational design of combination immunotherapies.