| Title | Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-Initiating Cells in C/EBPalpha Mutant AML. | | Author(s) | Bereshchenko O, Mancini E, Moore S, Bilbao D, Månsson R, Luc S, Grover A, Jacobsen SE, Bryder D, Nerlov C | | Institution | EMBL Mouse Biology Unit, Via Ramarini 32, 00015 Monterotondo, Italy. | | Source | Cancer Cell 2009 Nov 6; 16(5):390-400. | | Abstract | 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 19878871 |
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