An ShRNA Screen Identifies MEIS1 as a Driver of Malignant Peripheral Nerve Sheath Tumors

• Targeting over-expressed genes facilitates identification of sarcoma driver genes.
• We identify MEIS1 as a MPNST oncogene.
• MEIS1 suppresses p27Kip enabling MPNST survival.We identify MEIS1 as a sarcoma oncogene, and identify an additional 7 genes specific for survival of malignant peripheral nerve sheath cells. MEIS1 was frequently amplified or hypomethylated in human tumors, correlating with elevated MEIS1 gene and protein expression. MEIS1 enables cell cycle progression in these tumor cells through downregulation of expression of a pro-cell death protein p27Kip. Thus, inhibitors targeting cell cycle checkpoints and/or upregulating p27Kip may have therapeutic value for these patients, and perhaps for other tumor types in which MEIS1 is an oncogene.

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.