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We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBPalpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBPalpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBPalpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.

Original publication




Journal article


Cancer Cell

Publication Date





390 - 400


Animals, CCAAT-Enhancer-Binding Protein-alpha, Cell Cycle, Cell Growth Processes, Cell Line, Cell Transformation, Neoplastic, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Knockout