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

Ami V. Patel; Katherine E. Chaney; Kwangmin Choi; David A. Largaespada; Ashish R. Kumar; Nancy Ratner

doi:10.1016/j.ebiom.2016.06.007

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

Ami V. Patel, Katherine E. Chaney, Kwangmin Choi, David A. Largaespada, Ashish R. Kumar, Nancy Ratner

Pediatrics - Hematology

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Pages (from-to)	110-119
Number of pages	10
Journal	EBioMedicine
Volume	9
DOIs	https://doi.org/10.1016/j.ebiom.2016.06.007
State	Published - 2016

Bibliographical note

Funding 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.

Funding Information:
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.

Publisher Copyright:
© 2016

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

G0/G1 arrest
ID1
MEIS1
MPNST
RNAi
Sarcoma
p27

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@article{5885cfbcfccc49b886a702254923d36c,

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 p27Kip and maintaining cell survival.",

keywords = "G0/G1 arrest, ID1, MEIS1, MPNST, RNAi, Sarcoma, p27",

author = "Patel, {Ami V.} and Chaney, {Katherine E.} and Kwangmin Choi and Largaespada, {David A.} and Kumar, {Ashish R.} and Nancy Ratner",

note = "Funding 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2016 Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

year = "2016",

doi = "10.1016/j.ebiom.2016.06.007",

language = "English (US)",

volume = "9",

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journal = "EBioMedicine",

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AU - Patel, Ami V.

AU - Chaney, Katherine E.

AU - Choi, Kwangmin

AU - Largaespada, David A.

AU - Kumar, Ashish R.

AU - Ratner, Nancy

N1 - Funding 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. Funding Information: 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. Publisher Copyright: © 2016 Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - G0/G1 arrest

KW - ID1

KW - MEIS1

KW - MPNST

KW - RNAi

KW - Sarcoma

KW - p27

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JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -

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

Abstract

Bibliographical note

Keywords

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