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

Författare:
Publiceringsår: 2009
Språk: Engelska
Sidor: 390-400
Publikation/Tidskrift/Serie: Cancer Cell
Volym: 16
Nummer: 5
Dokumenttyp: Artikel
Förlag: Cell Press

Sammanfattning

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.

Disputation

Nyckelord

  • Medicine and Health Sciences

Övrigt

Published
Yes
  • ISSN: 1535-6108

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