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

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Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. / Porse, BT; Bryder, David; Theilgaard-Monch, K; Hasemann, MS; Anderson, Kristina; Damgaard, I; Jacobsen, Sten Eirik W; Nerlov, C.

In: Journal of Experimental Medicine, Vol. 202, No. 1, 2005, p. 85-96.

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Porse, BT ; Bryder, David ; Theilgaard-Monch, K ; Hasemann, MS ; Anderson, Kristina ; Damgaard, I ; Jacobsen, Sten Eirik W ; Nerlov, C. / Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. In: Journal of Experimental Medicine. 2005 ; Vol. 202, No. 1. pp. 85-96.

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TY - JOUR

T1 - Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage

AU - Porse, BT

AU - Bryder, David

AU - Theilgaard-Monch, K

AU - Hasemann, MS

AU - Anderson, Kristina

AU - Damgaard, I

AU - Jacobsen, Sten Eirik W

AU - Nerlov, C

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1084/jem.20050067

DO - 10.1084/jem.20050067

M3 - Article

VL - 202

SP - 85

EP - 96

JO - Journal of Experimental Medicine

T2 - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 1540-9538

IS - 1

ER -