Abstract
Tribbles homolog 2 (Trib2) was identified as a downregulated transcript in leukemic cells undergoing growth arrest. To investigate the effects of Trib2 in hematopoietic progenitors, mice were reconstituted with hematopoietic stem cells retrovirally expressing Trib2. Trib2-transduced bone marrow cells exhibited a growth advantage ex vivo and readily established factor-dependent cell lines. In vivo, Trib2-reconstituted mice uniformly developed fatal transplantable acute myelogenous leukemia (AML). In mechanistic studies, we found that Trib2 associated with and inhibited C/EBPalpha. Furthermore, Trib2 expression was elevated in a subset of human AML patient samples. Together, our data identify Trib2 as an oncogene that induces AML through a mechanism involving inactivation of C/EBPalpha.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Transplantation
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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 Line
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / physiology
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Leukemia, Myeloid, Acute / etiology
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Leukemia, Myeloid, Acute / metabolism*
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Mice
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Mice, Inbred C57BL
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Oncogenes
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Survival Rate
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Transplantation Chimera
Substances
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CCAAT-Enhancer-Binding Protein-alpha
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Intracellular Signaling Peptides and Proteins
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tribbles 2 protein, mouse
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Green Fluorescent Proteins
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Protein Serine-Threonine Kinases