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

Daniel R. Carrasco, Tim Fenton, Kumar Sukhdeo, Marina Protopopova, Miriam Enos, Mingjian J. You, Dolores Divicio, Cristina Nogueira, Jayne Stommel, Geraldine S. Pinkus, Christopher Fletcher, Jason L. Hornick, Webster K. Cavenee, Frank B. Furnari, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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, p16INK4A, and p14ARF, 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.

Original languageEnglish (US)
Pages (from-to)379-390
Number of pages12
JournalCancer Cell
Volume9
Issue number5
DOIs
StatePublished - May 2006
Externally publishedYes

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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