title: An ShRNA Screen Identifies MEIS1 as a Driver of Malignant Peripheral Nerve Sheath Tumors.
abstract: 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 p27(Kip) and maintaining cell survival.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229-0713, United States.
authors.forename: Ami V
authors.initials: AV
authors.lastname: Patel
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229-0713, United States.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Chaney
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229-0713, United States.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Division of Bone Marrow Transplantation & Immune Deficiency, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229-0713, United States.
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229-0713, United States. Electronic address: Nancy.Ratner@cchmc.org.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059585:G1 Phase Cell Cycle Checkpoints; D005838:Genotype; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*
chemical_list: C503688:CCNE2 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: G0/G1 arrest; ID1; MEIS1; MPNST; RNAi; Sarcoma; p27(Kip)