Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage
(2005) In Journal of Experimental Medicine 202(1). p.85-96- 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.... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/233437
- author
- Porse, BT ; Bryder, David LU ; Theilgaard-Monch, K ; Hasemann, MS ; Anderson, Kristina LU ; Damgaard, I ; Jacobsen, Sten Eirik W LU and Nerlov, C
- organization
- publishing date
- 2005
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Experimental Medicine
- volume
- 202
- issue
- 1
- pages
- 85 - 96
- publisher
- Rockefeller University Press
- external identifiers
-
- wos:000230215100009
- pmid:15983063
- scopus:22344437854
- ISSN
- 1540-9538
- DOI
- 10.1084/jem.20050067
- language
- English
- LU publication?
- yes
- id
- 5d33a706-3791-41e2-825b-0050d39bc9af (old id 233437)
- date added to LUP
- 2016-04-01 16:11:05
- date last changed
- 2022-07-09 19:25:12
@article{5d33a706-3791-41e2-825b-0050d39bc9af,
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.}},
author = {{Porse, BT and Bryder, David and Theilgaard-Monch, K and Hasemann, MS and Anderson, Kristina and Damgaard, I and Jacobsen, Sten Eirik W and Nerlov, C}},
issn = {{1540-9538}},
language = {{eng}},
number = {{1}},
pages = {{85--96}},
publisher = {{Rockefeller University Press}},
series = {{Journal of Experimental Medicine}},
title = {{Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage}},
url = {{http://dx.doi.org/10.1084/jem.20050067}},
doi = {{10.1084/jem.20050067}},
volume = {{202}},
year = {{2005}},
}