What question did this study set out to answer?

The study aims to characterize VSIR's function and regulation across hematological malignancies, particularly its epigenetic mechanisms and clinical implications.

March 4, 2026Open Access

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

Key Points

The study aims to characterize VSIR's function and regulation across hematological malignancies, particularly its epigenetic mechanisms and clinical implications.
Conducted multi-omics analyses of over 10,000 transcriptomes from diverse hematological malignancies.
Performed bisulfite sequencing on 130 clinical samples to validate promoter hypomethylation.
Utilized chromatin immunoprecipitation sequencing to identify transcriptional activation by KMT2A fusion proteins.
Evaluated the impact of Menin inhibitor treatment on KMT2A occupancy and VSIR expression.
VSIR expression was significantly upregulated in hematological malignancies, especially in myeloid leukemias.
Promoter hypomethylation increased from healthy controls to acute myeloid leukemia.
Menin inhibitor treatments reduced KMT2A occupancy and associated histone modifications at the VSIR promoter.
High VSIR levels correlated with specific immune regulatory pathways and predicted better responses to immunotherapy.
Elevated VSIR expression was linked to poorer outcomes in AML but better survival in DLBCL and MM.

Abstract

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.

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Cite This Study

Xu et al. (Mon,) studied this question.

synapsesocial.com/papers/69a7cdaed48f933b5eeda35e https://doi.org/https://doi.org/10.1038/s41598-026-41978-2

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