Cholesterol Biosynthesis is a Targetable Vulnerability of CEBPA-mutant Acute Myeloid Leukemia
Bi-allelic CEBPA mutations occur in 5-15% of acute myeloid leukemia (AML) patients. The precise molecular consequences of CEBPA mutations, especially in combination with frequently co-occurring mutations in TET2, WT1, and GATA2, remain incompletely understood. Here, we present a robust human model of CEBPA-mutant AML through gene editing of healthy bone marrow-derived hematopoietic stem cells. Loss of the CEBPA-p42 isoform expressed in healthy cells with concomitant upregulation of the leukemic CEBPA-p30 isoform resulted in a myeloproliferative phenotype. Concurrent loss-of-function mutations in TET2 or WT1 drove full leukemic transformation, while GATA2 haploinsufficiency promoted erythroid precursor accumulation without overt AML. Single-cell transcriptomics and low-input proteomics revealed enhanced myeloid output, increased interferon signaling and elevated cholesterol biosynthesis in leukemic cells. Targeting cholesterol synthesis enhanced chemosensitivity, highlighting a potential therapeutic vulnerability, particularly relevant for CEBPA-mutant patients harboring co-mutations in TET2 or WT1, which have poor outcomes. Statement of significanceInduction of CEBPA-p30 by CRISPR/Cas gene editing in healthy human BM HSCs drives overt AML in vivo. TET2 and WT1 loss accelerate leukemogenesis, while GATA2 haploinsufficiency redirects differentiation toward erythroid precursors potentially driving acute erythroid leukemia. CEBPA-p30 AML exhibits cholesterol biosynthesis dependency, revealing a therapeutic vulnerability to statins.