ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis

Christine Marie Hoeman, Francisco J. Cordero, Guo Hu, Katie Misuraca, Megan M. Romero, Herminio J. Cardona, Javad Nazarian, Rintaro Hashizume, Roger McLendon, Paul Yu, Daniele Procissi, Samantha L Gadd, Oren Josh Becher

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.

Original languageEnglish (US)
Article number1023
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

pathogenesis
Glioma
Tumors
tumors
mutations
deletion
Pediatrics
cultured cells
markers
lesions
inhibitors
Mutation
brain
Survival
Brain
incidence
Chemical activation
Cells
Brain Neoplasms
activation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Hoeman, Christine Marie ; Cordero, Francisco J. ; Hu, Guo ; Misuraca, Katie ; Romero, Megan M. ; Cardona, Herminio J. ; Nazarian, Javad ; Hashizume, Rintaro ; McLendon, Roger ; Yu, Paul ; Procissi, Daniele ; Gadd, Samantha L ; Becher, Oren Josh. / ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis. In: Nature communications. 2019 ; Vol. 10, No. 1.
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abstract = "Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25{\%} of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.",
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Hoeman, CM, Cordero, FJ, Hu, G, Misuraca, K, Romero, MM, Cardona, HJ, Nazarian, J, Hashizume, R, McLendon, R, Yu, P, Procissi, D, Gadd, SL & Becher, OJ 2019, ' ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis' Nature communications, vol. 10, no. 1, 1023. https://doi.org/10.1038/s41467-019-08823-9

ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis. / Hoeman, Christine Marie; Cordero, Francisco J.; Hu, Guo; Misuraca, Katie; Romero, Megan M.; Cardona, Herminio J.; Nazarian, Javad; Hashizume, Rintaro; McLendon, Roger; Yu, Paul; Procissi, Daniele; Gadd, Samantha L; Becher, Oren Josh.

In: Nature communications, Vol. 10, No. 1, 1023, 01.12.2019.

Research output: Contribution to journalArticle

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T1 - ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis

AU - Hoeman, Christine Marie

AU - Cordero, Francisco J.

AU - Hu, Guo

AU - Misuraca, Katie

AU - Romero, Megan M.

AU - Cardona, Herminio J.

AU - Nazarian, Javad

AU - Hashizume, Rintaro

AU - McLendon, Roger

AU - Yu, Paul

AU - Procissi, Daniele

AU - Gadd, Samantha L

AU - Becher, Oren Josh

PY - 2019/12/1

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