GSE117780
CEBPA-mutated leukemia is sensitive to genetic and pharmacological inhibition of the MLL complex
The gene encoding the transcription factor C/EBPa is mutated in 10-15% of all patients with de novo acute myeloid leukemia (AML). N-terminal CEBPA mutations cause selective ablation of full-length C/EBPa without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is not well understood. Here, we show that the SET/MLL histone methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. The oncogenic C/EBPa p30 isoform and MLL show global co-localization on chromatin and core SET/MLL complex components exhibit robust physical interaction with p30. We also show that C/EBPa p30-expressing cells require the expression of an intact MLL protein, as targeted CRISPR/Cas9-mediated mutagenesis results in proliferation arrest and myeloid differentiation. In line with this, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological inhibition of the SET/MLL complex. SET/MLL complex inhibition impairs proliferation, induces cell cycle arrest and causes apoptosis in mouse and human AML cells with CEBPA mutations. Global analysis of gene expression changes shows that inhibitor treatment restores myeloid differentiation potential in CEBPA-mutated cells. Finally, we identify the transcription factor GATA2 as a direct critical target of the cooperative gene regulation between p30 and MLL in CEBPA-mutated AML. Taken together, we show that C/EBPa p30 requires the SET/MLL complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the SET/MLL complex. These findings expand our understanding of CEBPA-mutated AML and identify the SET/MLL complex as a potential therapeutic target in this disease. Overall design: RNA-seq and ChIP-seq