Abstract A001: Loss of MLL1’s H3K4 methyltransferase activity activates a leukemic stem cell program characteristic of fusion-driven leukemias

Abstract Complete loss of MLL1’s H3K4 methyltransferase activity induces the leukemic stem cell program characteristic of fusion-driven leukemias, suggesting that fusion proteins may act through dominant disruption of wild-type MLL1. Chromosomal translocations involving the histone methyltransferase MLL1 (KMT2A) define a high-risk subset of acute leukemias, yet the mechanistic basis by which MLL1 fusion proteins initiate leukemogenesis remains unclear. We recently developed a human induced pluripotent stem cell (iPSC) model harboring a homozygous loss-of-function (LOF) mutation in MLL1 that unexpectedly recapitulates hallmark features of MLL1-rearranged leukemias, including global H3K4me3 hypermethylation, activation of HOXA9/MEIS1, and acquisition of a mixed-lineage stem-like phenotype (Kobrossy et al., Journal of Biological Chemistry (2024)). These findings demonstrate that loss of MLL1’s catalytic activity is sufficient to induce the transcriptional program normally associated with MLL1 fusions, supporting the hypothesis that MLL1 fusion proteins may drive leukemogenesis, at least in part, by dominantly interfering with the function or localization of wild type MLL1 encoded from the unaffected allele. We provide evidence that loss of MLL1 enables redistribution of the related H3K4 methyltransferase SETD1A, resulting in aberrant accumulation of H3K4me3 and transcriptional rewiring. This model offers a unique platform to dissect early events in leukemogenesis and to identify therapeutic strategies aimed at restoring epigenetic homeostasis. Together, these findings reveal a new conceptual framework in which fusion-driven leukemogenesis arises from destabilization of chromatin-modifying networks, rather than simple gain-of-function activity. Targeting epigenetic plasticity may therefore represent a promising therapeutic approach for MLL1-rearranged leukemias. AI Use Disclosure: Generative AI tools were used to assist with grammar and language editing of this abstract. The scientific content was conceived, written, and verified by the authors. Citation Format: Laila Kobrossy, Weiyi Xu, Chunling Zhang, Wenyi Feng, Christopher E. Turner, Michael S. Cosgrove. Loss of MLL1’s H3K4 methyltransferase activity activates a leukemic stem cell program characteristic of fusion-driven leukemias [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A001.