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Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage

In English

Författare

  • BT Porse
  • David Bryder
  • K Theilgaard-Monch
  • MS Hasemann
  • Kristina Anderson
  • I Damgaard
  • Sten Eirik W Jacobsen
  • C Nerlov

Summary, in English

CCAAT/enhancer binding protein (C/EBP)alpha is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBP alpha to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow ( BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations - all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count - normally associated with AML - were absent. These results show that disrupting the cell cycle regulatory function of C/EBP alpha is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.

Avdelning/ar

Publiceringsår

2005

Språk

Engelska

Sidor

85-96

Publikation/Tidskrift/Serie

Journal of Experimental Medicine

Volym

202

Issue

1

Dokumenttyp

Artikel i tidskrift

Förlag

Rockefeller University Press

Ämne

  • Immunology in the medical area

Status

Published

Forskningsgrupp

  • Immunology

ISBN/ISSN/Övrigt

  • ISSN: 1540-9538