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PMID: 15983063 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of experimental medicine ·Vol. 202 ·No. 1 ·2005-07-04 ·Pages 85-96

Porse BT, Bryder D, Theilgaard-Mönch K, Hasemann MS, Anderson K, Damgaard I, Jacobsen SE, Nerlov C

Abstract

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.

MeSH Terms
Animals Bone Marrow Transplantation CCAAT-Enhancer-Binding Protein-alpha/genetics,physiology Cell Cycle/genetics,physiology Cell Differentiation Cell Proliferation Cell Transformation, Neoplastic/genetics Granulocytes/cytology Humans Leukemia, Myeloid, Acute/genetics Mice Mice, Inbred C57BL Mice, Mutant Strains Mutation Myeloid Progenitor Cells/cytology Myeloproliferative Disorders/etiology,genetics,pathology Neutrophils/cytology Phenotype
Chemicals
CCAAT-Enhancer-Binding Protein-alpha
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Porse Bo T
Laboratory of Gene Therapy Research, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
Bryder David
Theilgaard-Mönch Kim
Hasemann Marie S
Anderson Kristina
Damgaard Inge
Jacobsen Sten Eirik W
Nerlov Claus
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20050067
Published
2005-07-04
Epub
2005-00-27
Pages
85-96
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2212897
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20050067 PMC Full Text View journal details
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