TY - JOUR

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

C2 - 15983063

VL - 202

SP - 85

EP - 96

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

SN - 0022-1007

IS - 1

ER -