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Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by profound transcriptional dysregulation and impaired hematopoietic differentiation. While differentiation therapy has revolutionized treatment in acute promyelocytic leukemia (APL), analogous strategies in non-APL AML remain elusive. Here, we identify ZMIZ1 (Zinc finger MIZ domain-containing protein 1) as a previously unrecognized transcriptional co-regulator that enforces differentiation blockade in AML from a targeted CRISPR-Cas9 screen. ZMIZ1 expression is elevated in AML patients and correlates with adverse outcomes. Genetic ablation of ZMIZ1 in leukemic cells induces terminal differentiation, reduces leukemia cell stemness, restores anti-leukemic immune responses, and significantly prolongs survival in murine AML models. Mechanistically, ZMIZ1 forms phase-separated nuclear condensates and maintains the super-enhancer architecture of genes critical for hematopoietic identity and immune evasion. Integrated Hi-C and ChIP-seq analyses reveal that ZMIZ1 cooperates with MEF2D (Myocyte-specific enhancer factor 2D) to promote enhancer-promoter looping and transcriptional output. Finally, we report the development of small-compounds potentially targeting ZMIZ1 with high binding affinity, selective on-target activity, and potent in vivo efficacy in both the murine AML model and AML organoids. Collectively, these findings uncover ZMIZ1 as a targetable epigenetic vulnerability in AML, underscoring its potential as a promising therapeutic target for differentiation-based treatment strategies.