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

Författare:
Publiceringsår: 2005
Språk: Engelska
Sidor: 85-96
Publikation/Tidskrift/Serie: JOURNAL OF EXPERIMENTAL MEDICINE
Volym: 202
Nummer: 1
Dokumenttyp: Artikel
Förlag: ROCKEFELLER UNIVERSITY PRESS

Sammanfattning

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.

Disputation

Nyckelord

  • Biology and Life Sciences
  • Medicine and Health Sciences

Övrigt

Published
Yes
  • ISSN: 0022-1007

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