Abstract 7043: HMGA1 Epigenetic Regulators Drive Relapse in Pediatric B-Cell Leukemia By Amplifying ETV5 and Stemness Networks

Abstract Despite advances in therapy for pediatric B-cell acute lymphoblastic leukemia (pB-ALL), relapse remains a leading cause of death in children with cancer. The gene encoding the High Mobility Group A1 (HMGA1) chromatin regulator is highly expressed in stem cells and hematologic malignancies where high levels portend poor outcomes. In pB-ALL, HMGA1 is overexpressed with highest levels at relapse. Transgenic mice overexpressing Hmga1 in lymphoid cells develop aggressive leukemia. To determine how HMGA1 functions in relapsed pB-ALL, we performed multiomic analyses. Here, we uncover a previously unknown role for HMGA1 as an epigenetic gatekeeper of stemness transcriptional networks at relapse. Strikingly, silencing HMGA1 expression via CRISPR or short hairpin RNA decreases proliferation and clonogenicity in vitro while disrupting engraftment and prolonging survival in vivo. Multiomics analyses revealed transcriptional networks governed by HMGA1 that regulate proliferation (G2M checkpoint, E2F), RAS/ERK signaling, hematopoietic stem cells (HSCs), and ETS variant 5 transcription factor (ETV5) targets. CRISPR-mediated ETV5 gene silencing recapitulates effects of HMGA1 silencing in pB-ALL cell lines. Further, restoring ETV5 expression in pB-ALL cell lines with HMGA1 silencing partially rescues anti-leukemogenic effects of HMGA1 depletion. Mechanistically, HMGA1 binds to AT-rich regions within the ETV5 promoter and recruits activating histone marks to induce ETV5. Moreover, HMGA1 and ETV5 are co-expressed and up-regulated in primary blasts from children with relapsed pB-ALL where high HMGA1 correlates inversely with time to relapse. Artificial intelligence predicted that the histone deacetylase inhibitor (HDACi), vorinostat, targets HMGA1-ETV5 gene networks. In PDX models with pB-ALL blasts from relapse, we found that vorinostat enhances responses to standard B-ALL therapy (dexamethasone, vincristine), depleting circulating blasts and disrupting leukemic engraftment. Our findings reveal HMGA1 as an epigenetic switch that activates ETV5 and HSC gene networks in relapsed pB-ALL and rational therapeutic target to treat or prevent relapse. Citation Format: Linda M. S. Resar, Jung-Hyun Kim, Andrei Thomas-Tikonenko, Sarah Tasian. HMGA1 Epigenetic Regulators Drive Relapse in Pediatric B-Cell Leukemia By Amplifying ETV5 and Stemness Networks [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 7043.