Abstract
Histiocytic sarcoma (HS) is a rare malignant proliferation of histiocytes of uncertain molecular pathogenesis. Here, genetic analysis of coincident loss of Pten and Ink4a/Arf tumor suppressors in the mouse revealed a neoplastic phenotype dominated by a premalignant expansion of biphenotypic myelolymphoid cells followed by the development of HS. Pten protein loss occurred only in the histiocytic portion of tumors, suggesting a stepwise genetic inactivation in the generation of HS. Similarly, human HS showed genetic or epigenetic inactivation of PTEN, p16(INK4A), and p14(ARF), supporting the relevance of this genetically engineered mouse model of HS. These genetic and translational observations establish a cooperative role of Pten and Ink4a/Arf in the development of HS and provide mechanistic insights into the pathogenesis of human HS.
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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Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Histiocytic Disorders, Malignant / immunology
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Histiocytic Disorders, Malignant / pathology*
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Homeostasis
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Humans
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Immunophenotyping
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Lymphocytes / immunology*
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Methylation
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Mice
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Mutation / genetics
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Myeloid Cells / immunology*
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PTEN Phosphohydrolase / deficiency
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PTEN Phosphohydrolase / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Sarcoma / immunology
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Sarcoma / pathology*
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Tumor Suppressor Protein p14ARF / deficiency
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Tumor Suppressor Protein p14ARF / metabolism*
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Tumor Suppressor Protein p14ARF
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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PTEN Phosphohydrolase