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

Author

Listed:
  • Christine M. Hoeman

    (Northwestern University)

  • Francisco J. Cordero

    (Duke University)

  • Guo Hu

    (Baylor College of Medicine)

  • Katie Misuraca

    (Duke University)

  • Megan M. Romero

    (Northwestern University)

  • Herminio J. Cardona

    (Northwestern University)

  • Javad Nazarian

    (George Washington University)

  • Rintaro Hashizume

    (Northwestern University
    Northwestern University
    Northwestern University)

  • Roger McLendon

    (Duke University Medical Center
    Duke University Medical Center)

  • Paul Yu

    (Brigham and Women’s Hospital)

  • Daniele Procissi

    (Northwestern University)

  • Samantha Gadd

    (Ann & Robert H. Lurie Children’s Hospital)

  • Oren J. Becher

    (Northwestern University
    Northwestern University
    Northwestern University
    Ann & Robert H. Lurie Children’s Hospital)

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.

Suggested Citation

  • 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 & Samant, 2019. "ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08823-9
    DOI: 10.1038/s41467-019-08823-9
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    Cited by:

    1. Yeon-Suk Yang & Jung-Min Kim & Jun Xie & Sachin Chaugule & Chujiao Lin & Hong Ma & Edward Hsiao & Jaehyoung Hong & Hyonho Chun & Eileen M. Shore & Frederick S. Kaplan & Guangping Gao & Jae-Hyuck Shim, 2022. "Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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