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

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9 Citas (Scopus)


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.

Idioma originalEnglish (US)
Número de artículoeaau8389
PublicaciónScience Advances
EstadoPublished - abr 24 2019
Publicado de forma externa

ASJC Scopus subject areas

  • General


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