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

Bo T Porse; David Bryder; Kim Theilgaard-Mönch; Marie S Hasemann; Kristina Anderson; Inge Damgaard; Sten Eirik W Jacobsen; Claus Nerlov

doi:10.1084/jem.20050067

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

Bo T Porse, David Bryder, Kim Theilgaard-Mönch, Marie S Hasemann, Kristina Anderson, Inge Damgaard, Sten Eirik W Jacobsen, Claus Nerlov

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

95 Citationer (Scopus)

Abstract

Udgivelsesdato: 2005-Jul-4

Originalsprog	Engelsk
Tidsskrift	Journal of Experimental Medicine
Vol/bind	202
Udgave nummer	1
Sider (fra-til)	85-96
Antal sider	11
ISSN	0022-1007
DOI	https://doi.org/10.1084/jem.20050067
Status	Udgivet - 2005

Bibliografisk note

Keywords: Animals; Bone Marrow Transplantation; CCAAT-Enhancer-Binding Protein-alpha; Cell Cycle; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Granulocytes; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Myeloid Progenitor Cells; Myeloproliferative Disorders; Neutrophils; Phenotype

Adgang til dokumentet

10.1084/jem.20050067

Citationsformater

Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. / Porse, Bo T; Bryder, David; Theilgaard-Mönch, Kim; Hasemann, Marie S; Anderson, Kristina; Damgaard, Inge; Jacobsen, Sten Eirik W; Nerlov, Claus.

I: Journal of Experimental Medicine, Bind 202, Nr. 1, 2005, s. 85-96.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

@article{8e43b2d0588c11dd8d9f000ea68e967b,

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

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, {Bo T} and David Bryder and Kim Theilgaard-M{\"o}nch and Hasemann, {Marie S} and Kristina Anderson and Inge Damgaard and Jacobsen, {Sten Eirik W} and Claus Nerlov",

note = "Keywords: Animals; Bone Marrow Transplantation; CCAAT-Enhancer-Binding Protein-alpha; Cell Cycle; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Granulocytes; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Myeloid Progenitor Cells; Myeloproliferative Disorders; Neutrophils; Phenotype",

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

AU - Porse, Bo T

AU - Bryder, David

AU - Theilgaard-Mönch, Kim

AU - Hasemann, Marie S

AU - Anderson, Kristina

AU - Damgaard, Inge

AU - Jacobsen, Sten Eirik W

AU - Nerlov, Claus

N1 - Keywords: Animals; Bone Marrow Transplantation; CCAAT-Enhancer-Binding Protein-alpha; Cell Cycle; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Granulocytes; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Myeloid Progenitor Cells; Myeloproliferative Disorders; Neutrophils; Phenotype

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 - Journal article

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VL - 202

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JO - The Journal of Experimental Medicine

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