Abstract 1432: HMGA1 disrupts 3D genome architecture and chromatin looping to repress MHC-II genes and drive immune evasion

Abstract While targeting immune escape has revolutionized cancer therapy, many tumors, such as acute myeloid leukemia (AML), develop strategies to evade a T-cell mediated immune attack. Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders at high risk for transformation to secondary AML (sAML). Leukemic transformation in MPN is almost universally fatal and targetable mechanisms have remained elusive. The High Mobility Group A1 (HMGA1) gene encodes an architectural transcription factor that binds to DNA at AT-rich sequences where it recruits chromatin complexes to modulate gene expression. HMGA1 is highly expressed during embryogenesis and in adult stem cells, but silenced in differentiated cells. HMGA1 becomes re-expressed in aggressive cancers where high levels portend adverse outcomes. We previously discovered that HMGA1 is overexpressed in MPN with highest levels after leukemic transformation. Further, our studies in murine models reveal that HMGA1 is required for MPN progression to sAML. To determine how HMGA1 functions in MPN transformation, we performed multiomic analyses to assess gene expression and chromatin state in MPN AML cells. Here, we uncover a novel role for HMGA1 chromatin regulators as drivers of immune escape by modulating three-dimensional (3D) genome architecture to repress antigen-presenting (AP) genes that trigger a T cell-mediated anti-tumor attack. Mechanistically, HMGA1 binds throughout the class II major histocompatibility complex (MHC-II) locus at key regulatory regions and recruits repressive histones to compact chromatin. HMGA1-mediated chromatin compaction at MHC-II enhancers disrupts binding by the genome organizer, CCCTC binding factor (CTCF), thereby preventing CTCF from orchestrating 3D chromatin loops to activate AP genes and stimulate a T-cell mediated anti-tumor immune attack. Using artificial intelligence, we predicted that the histone deacetylase inhibitor, entinostat, targets HMGA1 networks. Strikingly, HMGA1 gene silencing or treatment with entinostat restores CTCF-mediated chromatin loops and induces AP genes, resulting in a robust T cell-mediated attack on MPN AML cells. Single cell transcriptomics in patient samples demonstrate that HMGA1 correlates inversely with MHC-II repression, particularly in AML with bi-allelic TP53 mutations, demonstrating the relevance of this HMGA1 network in humans. Together, our data illuminate the HMGA1-MHC-II axis as a promising immunotherapeutic target to activate AP genes and trigger a T cell anti-tumor attack in MPN AML and potentially other cancers overexpressing HMGA1. Citation Format: Linda M. S. Resar, Joseph Kim, Audrey Supreme, Li Z. Luo, Bailey West, Isha Maloo, Jung-Hyun Kim, Leslie Cope, Jerry Spivak. HMGA1 disrupts 3D genome architecture and chromatin looping to repress MHC-II genes and drive immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1432.