The t(7;12)(q36;p13) AML subtype in pediatric patients is associated with the upregulation of homeodomain protein MNX1 as the initiating event for leukemogenesis. In this study, we investigated the downstream targets of MNX1 and their relationship to MNX1-induced histone modifications. Using a comprehensive approach combining TMT mass spectrometry, RNA-sequencing, qPCR, antibody-guided chromatin tagmentation sequencing (ACT-Seq), assay for transposase-accessible chromatin using sequencing (ATAC- seq), and chromatin immunoprecipitation assay (ChIP) followed by qPCR, we identified Pbxip1 along with its associated transcription factor Pbx1, and Pbx4 as downstream targets of MNX1. MNX1 binding to the Pbx1 promoter triggered its transcriptional activation, associated with increased H3K4me3 and decreased H3K27me3 at the Pbx1promoter. Despite the transient nature of MNX1’s promoter interaction, these histone marks persisted, suggesting a “hit-and-run” epigenetic remodeling mechanism. Enrichment of Pbx motifs within MNX1-induced H3K4me1, H3K4me3, and ATAC-seq peaks underscores the role of the Pbx family in MNX1-mediated chromatin dynamics. This was further confirmed by showing that MNX1-induced Pbx1expression could be downregulated using Sinefungin, a pan-methyltransferase inhibitor, that also prevents MNX1-driven leukemia. Our findings provide insights into how MNX1-driven epigenetic modifications are connected to its downstream targets and may offer new avenues for therapeutic intervention in t(7;12) AML.