Abstract
Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CCAAT-Enhancer-Binding Protein-alpha / deficiency
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CCAAT-Enhancer-Binding Protein-alpha / genetics
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CCAAT-Enhancer-Binding Protein-alpha / metabolism*
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Cell Differentiation
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Disease Progression
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic*
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Granulocytes / cytology
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Leukemia, Myelomonocytic, Acute / genetics*
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Leukemia, Myelomonocytic, Acute / pathology*
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Macrophage-1 Antigen / metabolism
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Mice
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Mice, Knockout
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Models, Biological*
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Mutant Proteins / metabolism*
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Myeloid Progenitor Cells / pathology
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Neoplasm Transplantation
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Phenotype
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins c-kit / metabolism
Substances
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CCAAT-Enhancer-Binding Protein-alpha
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Macrophage-1 Antigen
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Mutant Proteins
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Protein Isoforms
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Proto-Oncogene Proteins c-kit