RUNX represses <i>Pmp22</i> to drive neurofibromagenesis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31032403.
- Also identified by DOI 10.1126/sciadv.aau8389 and PMC identifier 6482019.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>Runx1</i> and <i>Runx3</i> in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (<i>Pmp22/Gas3</i>) related to neurofibroma initiation. Knockdown of <i>Pmp22</i> with short hairpin RNAs increased <i>Runx1<sup>fl/fl</sup>;Runx3<sup>fl/fl</sup>;Nf1<sup>fl/fl</sup>;DhhCre</i> tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of <i>Pmp22</i> in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of <i>Pmp22</i> 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 <i>Pmp22</i> in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.
Medical subject headings
- Core Binding Factor Alpha 2 Subunit
- Core Binding Factor Alpha 3 Subunit
- Gene Expression Regulation, Neoplastic
- Myelin Proteins
- Neurofibroma