The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans

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 myelolym...

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Bibliographic Details
Published in:Cancer cell 2006-05, Vol.9 (5), p.379-390
Main Authors: Carrasco, Daniel R., Fenton, Tim, Sukhdeo, Kumar, Protopopova, Marina, Enos, Miriam, You, Mingjian J., Divicio, Dolores, Nogueira, Cristina, Stommel, Jayne, Pinkus, Geraldine S., Fletcher, Christopher, Hornick, Jason L., Cavenee, Webster K., Furnari, Frank B., DePinho, Ronald A.
Format: Article
Language:English
Subjects:
Animals
CELLCYCLE
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases - metabolism
Histiocytic Disorders, Malignant - immunology
Histiocytic Disorders, Malignant - pathology
Homeostasis
Humans
Immunophenotyping
Lymphocytes - immunology
Methylation
Mice
Mutation - genetics
Myeloid Cells - immunology
Proto-Oncogene Proteins c-akt - metabolism
PTEN Phosphohydrolase - deficiency
PTEN Phosphohydrolase - metabolism
Sarcoma - immunology
Sarcoma - pathology
Tumor Suppressor Protein p14ARF - deficiency
Tumor Suppressor Protein p14ARF - metabolism
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2006.03.028