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

EBioMedicine

David A. Largaespada¹  Ashish R. Kumar²  Katherine E. Chaney³  Kwangmin Choi³  Ami V. Patel³  Nancy Ratner³ 

[1] Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States;Division of Bone Marrow Transplantation & Immune Deficiency, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229-0713, United States;Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229-0713, United States;

关键词: MPNST;    MEIS1;    ID1;    RNAi;    p27Kip;    G0/G1 arrest;    Sarcoma;   

DOI  :  10.1016/j.ebiom.2016.06.007

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown