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Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-initiating Cells in C/EBP alpha Mutant AML

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Author

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

Summary, in English

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/EBP alpha 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/EBP alpha 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/EBP alpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.

Publishing year

2009

Language

English

Pages

390-400

Publication/Series

Cancer Cell

Volume

16

Issue

5

Document type

Journal article

Publisher

Cell Press

Topic

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1878-3686