Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML

Oxana Bereshchenko, Elena Mancini, Susan Moore, Daniel Bilbao, Robert Månsson, Sidinh Luc, Amit Grover, Sten Eirik W Jacobsen, David Bryder, Claus Nerlov

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)390-400
Number of pages11
JournalCancer Cell
Volume16
Issue number5
Early online date2 Nov 2009
DOIs
Publication statusE-pub ahead of print - 2 Nov 2009

Keywords

  • Cell cycle
  • Stem cell

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