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

Research output: Contribution to journalArticle

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/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.

Details

Authors
  • Oxana Bereshchenko
  • Elena Mancini
  • Susan Moore
  • Daniel Bilbao
  • Robert Månsson
  • Sidinh Luc
  • Amit Grover
  • Sten Eirik W Jacobsen
  • David Bryder
  • Claus Nerlov
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)390-400
JournalCancer Cell
Volume16
Issue number5
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes