Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are a major source of mortality in neurofibromatosis type 1 (NF1) patients. To identify MPNST driver genes, we performed a lentiviral short hairpin (sh) RNA screen, targeting all 130 genes up-regulated in neurofibroma and MPNSTs versus normal human nerve Schwann cells. NF1 mutant cells show activation of RAS/MAPK signaling, so a counter-screen in RAS mutant carcinoma cells was performed to exclude common RAS-pathway driven genes. We identified 7 genes specific for survival of MPSNT cells, including MEIS1. MEIS1 was frequently amplified or hypomethylated in human MPSNTs, correlating with elevated MEIS1 gene expression. In MPNST cells and in a genetically engineered mouse model, MEIS1 expression in developing nerve glial cells was necessary for MPNST growth. Mechanistically, MEIS1 drives MPNST cell growth via the transcription factor ID1, thereby suppressing expression of the cell cycle inhibitor p27Kip and maintaining cell survival.
Bibliographical noteFunding Information:
DL is a co-founder, consultant, and co-owner of NeoClone Biotechnologies, Inc., Discovery Genomics, Inc., (recently acquired by Immusoft, Inc.), and B-MoGen Biotechnologies, Inc. Some of his laboratory work is funded by Genentech, Inc. He is a consultant to Surrogen, Inc., a company making porcine models of human diseases.
This work was supported by NIH grants R01NS28840 to NR and R01HL111192 to ARK. AVP was supported by Postdoctoral Fellowship W81XWH1110144 from the DAMD Program on Neurofibromatosis and a Pelotonia Postdoctoral Award.
Copyright 2017 Elsevier B.V., All rights reserved.
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