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

Christine M 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 Gadd; Oren J Becher

doi:10.1038/s41467-019-08823-9

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

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

Authors

Christine M Hoeman¹, Francisco J Cordero², Guo Hu³, Katie Misuraca⁴, Megan M Romero¹, Herminio J Cardona¹, Javad Nazarian⁵, Rintaro Hashizume^{6

7

8}, Roger McLendon^{9

10}, Paul Yu¹¹, Daniele Procissi¹², Samantha Gadd¹³, Oren J Becher^{14

15

16

17}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors, Type I / genetics
Activin Receptors, Type I / metabolism*
Animals
Astrocytoma / drug therapy
Astrocytoma / genetics
Astrocytoma / metabolism*
Astrocytoma / pathology
Brain Stem Neoplasms / drug therapy
Brain Stem Neoplasms / genetics
Brain Stem Neoplasms / metabolism*
Brain Stem Neoplasms / pathology
Carrier Proteins / pharmacology
Cell Line, Tumor / drug effects
Cell Proliferation
Disease Models, Animal
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / genetics
Genome, Human / genetics*
Glioma / drug therapy
Glioma / genetics
Glioma / metabolism*
Glioma / pathology
Histones / genetics
Histones / metabolism*
Humans
Mice
Mutation
Platelet-Derived Growth Factor / metabolism
Pyrazoles / pharmacology
Pyrimidines / pharmacology
Quinolines / pharmacology
STAT3 Transcription Factor / metabolism
Signal Transduction

Substances

Carrier Proteins
Histones
LDN-212854
Platelet-Derived Growth Factor
Pyrazoles
Pyrimidines
Quinolines
STAT3 Transcription Factor
STAT3 protein, human
platelet-derived growth factor A
noggin protein
ACVR1 protein, human
Activin Receptors, Type I

Abstract

Publication types

MeSH terms

Substances

Grants and funding