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; MiOk 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

Sci Adv. 2019 Apr 24;5(4):eaau8389. doi: 10.1126/sciadv.aau8389. eCollection 2019 Apr.

Authors

Ashley Hall¹, Kwangmin Choi¹, Wei Liu¹, Jonathan Rose¹, Chuntao Zhao¹, Yanan Yu^{1

2}, Youjin Na¹, Yuqi Cai¹, Robert A Coover¹, Yi Lin¹, Eva Dombi³, MiOk Kim⁴, Ditsa Levanon⁵, Yoram Groner⁵, Elisa Boscolo^{1

6}, Dao Pan^{1

6}, P Paul Liu⁷, Q Richard Lu^{1

6}, Nancy Ratner^{1

6}, Gang Huang^{1

6}, Jianqiang Wu^{1

6}

Affiliations

¹ Cincinnati Children's Hospital Medical Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, University of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
² Department of Cancer and Cell Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
³ Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
⁴ Department of Epidemiology and Biostatistics, UCSF, Box 0128, 1450 3rd St. Suite 285, San Francisco, CA 94143, USA.
⁵ Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
⁶ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁷ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

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 Runx1^fl/fl;Runx3^fl/fl;Nf1^fl/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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alleles
Animals
Base Sequence
Cell Proliferation
Cell Survival
Core Binding Factor Alpha 2 Subunit / metabolism*
Core Binding Factor Alpha 3 Subunit / metabolism*
Core Binding Factor beta Subunit / metabolism
Female
Gene Deletion
Gene Expression Regulation, Neoplastic*
Humans
Male
Mice
Mice, Nude
Myelin Proteins / metabolism*
Neurofibroma / metabolism*
Promoter Regions, Genetic
RNA, Small Interfering / metabolism
Schwann Cells / metabolism
Signal Transduction
Transcriptome

Substances

CBFB protein, human
Cbfb protein, mouse
Core Binding Factor Alpha 2 Subunit
Core Binding Factor Alpha 3 Subunit
Core Binding Factor beta Subunit
Myelin Proteins
PMP22 protein, human
Pmp22 protein, mouse
RNA, Small Interfering
RUNX1 protein, human
Runx1 protein, mouse
Runx3 protein, human
Runx3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding