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 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.
Carrasco
Daniel R
DR
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Fenton
Tim
T
Sukhdeo
Kumar
K
Protopopova
Marina
M
Enos
Miriam
M
You
Mingjian J
MJ
Di Vizio
Dolores
D
Divicio
Dolores
D
Nogueira
Cristina
C
Stommel
Jayne
J
Pinkus
Geraldine S
GS
Fletcher
Christopher
C
Hornick
Jason L
JL
Cavenee
Webster K
WK
Furnari
Frank B
FB
Depinho
Ronald A
RA
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015620:Histiocytic Disorders, Malignant / Q000276:immunology / Q000473:pathology*; D006706:Homeostasis; D006801:Humans; D016130:Immunophenotyping; D008214:Lymphocytes / Q000276:immunology*; D008745:Methylation; D051379:Mice; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000276:immunology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012509:Sarcoma / Q000276:immunology / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase