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Nat Commun. 2019 Mar 4;10(1):1023. doi: 10.1038/s41467-019-08823-9.

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

Author information

1
Department of Pediatrics, Northwestern University, Chicago, IL, 60611, USA.
2
GI Oncology Research Unit, Duke Cancer Institute, Duke University, Durham, NC, 27710, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
4
Department of Pediatrics, Duke University, Durham, NC, 27710, USA.
5
Department of Integrative Systems Biology, Children's National Medical Center, George Washington University, Washington, DC, 20010, USA.
6
Department of Neurosurgery, Northwestern University, Chicago, IL, 60611, USA.
7
Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, 60611, USA.
8
Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60611, USA.
9
Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.
10
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, 27710, USA.
11
Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
12
Department of Radiology, Northwestern University, Chicago, IL, 60611, USA.
13
Department of Pathology, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, 60611, USA.
14
Department of Pediatrics, Northwestern University, Chicago, IL, 60611, USA. oren.becher@northwestern.edu.
15
Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, 60611, USA. oren.becher@northwestern.edu.
16
Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60611, USA. oren.becher@northwestern.edu.
17
Division of Hematology Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, 60611, USA. oren.becher@northwestern.edu.

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.

PMID:
30833574
PMCID:
PMC6399349
DOI:
10.1038/s41467-019-08823-9
[Indexed for MEDLINE]
Free PMC Article

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