RUNX represses Pmp22 to drive neurofibromagenesis

Ashley Hall; Kwangmin Choi; Wei Liu; Jonathan Rose; Chuntao Zhao; Yanan Yu; Youjin Na; Yuqi Cai; Robert A. Coover; Yi Lin; Eva Dombi; Mi Ok Kim; Ditsa Levanon; Yoram Groner; Elisa Boscolo; Dao Pan; P. Paul Liu; Q. Richard Lu; Nancy Ratner; Gang Huang; Jianqiang Wu

doi:10.1126/sciadv.aau8389

RUNX represses Pmp22 to drive neurofibromagenesis

Ashley Hall, Kwangmin Choi, Wei Liu, Jonathan Rose, Chuntao Zhao, Yanan Yu, Youjin Na, Yuqi Cai, Robert A. Coover, Yi Lin, Eva Dombi, Mi Ok Kim, Ditsa Levanon, Yoram Groner, Elisa Boscolo, Dao Pan, P. Paul Liu, Q. Richard Lu, Nancy Ratner, Gang HuangJianqiang Wu

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

11 Scopus citations

Abstract

Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of Runx1 and Runx3 in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to neurofibroma initiation. Knockdown of Pmp22 with short hairpin RNAs increased Runx1fl/fl;Runx3fl/fl;Nf1fl/fl;DhhCre tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of Pmp22 to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.

Original language	English (US)
Article number	eaau8389
Journal	Science Advances
Volume	5
Issue number	4
DOIs	https://doi.org/10.1126/sciadv.aau8389
State	Published - Apr 24 2019
Externally published	Yes

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title = "RUNX represses Pmp22 to drive neurofibromagenesis",

abstract = "Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of Runx1 and Runx3 in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to neurofibroma initiation. Knockdown of Pmp22 with short hairpin RNAs increased Runx1fl/fl;Runx3fl/fl;Nf1fl/fl;DhhCre tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of Pmp22 to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.",

author = "Ashley Hall and Kwangmin Choi and Wei Liu and Jonathan Rose and Chuntao Zhao and Yanan Yu and Youjin Na and Yuqi Cai and Coover, {Robert A.} and Yi Lin and Eva Dombi and Kim, {Mi Ok} and Ditsa Levanon and Yoram Groner and Elisa Boscolo and Dao Pan and Liu, {P. Paul} and Lu, {Q. Richard} and Nancy Ratner and Gang Huang and Jianqiang Wu",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors.",

year = "2019",

month = apr,

day = "24",

doi = "10.1126/sciadv.aau8389",

language = "English (US)",

volume = "5",

journal = "Science Advances",

issn = "2375-2548",

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TY - JOUR

T1 - RUNX represses Pmp22 to drive neurofibromagenesis

AU - Hall, Ashley

AU - Choi, Kwangmin

AU - Liu, Wei

AU - Rose, Jonathan

AU - Zhao, Chuntao

AU - Yu, Yanan

AU - Na, Youjin

AU - Cai, Yuqi

AU - Coover, Robert A.

AU - Lin, Yi

AU - Dombi, Eva

AU - Kim, Mi Ok

AU - Levanon, Ditsa

AU - Groner, Yoram

AU - Boscolo, Elisa

AU - Pan, Dao

AU - Liu, P. Paul

AU - Lu, Q. Richard

AU - Ratner, Nancy

AU - Huang, Gang

AU - Wu, Jianqiang

PY - 2019/4/24

Y1 - 2019/4/24

N2 - Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of Runx1 and Runx3 in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to neurofibroma initiation. Knockdown of Pmp22 with short hairpin RNAs increased Runx1fl/fl;Runx3fl/fl;Nf1fl/fl;DhhCre tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of Pmp22 to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.

AB - Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of Runx1 and Runx3 in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to neurofibroma initiation. Knockdown of Pmp22 with short hairpin RNAs increased Runx1fl/fl;Runx3fl/fl;Nf1fl/fl;DhhCre tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of Pmp22 to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.

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DO - 10.1126/sciadv.aau8389

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JO - Science Advances

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ER -

RUNX represses Pmp22 to drive neurofibromagenesis

Abstract

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