Abstract Across different subtypes, Acute myeloid leukemia (AML) is a malignancy of proliferating myeloid cells that fail to differentiate. The failure of AML cells to respond to physiological differentiation cues remains a critical challenge despite extensive efforts, with few exceptions. We performed a CRISPR screen for transcriptional and epigenetic regulators of differentiation in AML cells. Our findings identified the roles of multiple components of the mediator complex, STAGA complex, and different transcription factors. We applied a Perturb-seq strategy which revealed how each lesion affects differentiation trajectories, uncovering shared and unique pathways in AML. Interestingly, we found multiple distinct transcriptional trajectories of differentiation in AML cells. We have validated these findings through additional in vitro and in vivo evaluations and are exploring their therapeutic relevance. Together, our results highlight key components of transcription regulatory complexes that are required to maintain the differentiation block in AML and pinpoint new targets for interventions. Citation Format: Sagarajit Mohanty, Jieun Jeong, Soumya Sharma, Daniel Cizin, Jun Ho Lee, Wenbin Xiao, Richard Koche, Thomas Norman, Hans-Guido Wendel. Transcriptional control of myeloid differentiation trajectories in AML abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7246.
Mohanty et al. (Fri,) studied this question.