1. Cancer Biology
  2. Developmental Biology and Stem Cells
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Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth

  1. Tiemo J Klisch  Is a corresponding author
  2. Anna Vainshtein
  3. Akash J Patel
  4. Huda Y Zoghbi
  1. Texas Children's Hospital, United States
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Cite as: eLife 2017;6:e31181 doi: 10.7554/eLife.31181

Abstract

Treatment for medulloblastoma, the most common malignant brain tumor in children, remains limited to surgical resection, radiation, and traditional chemotherapy; with long-term survival as low as 50-60% for Sonic Hedgehog (Shh)-type medulloblastoma. We have shown that the transcription factor Atonal homologue 1 (Atoh1) is required for Shh-type medulloblastoma development in mice. To determine whether reducing either Atoh1 levels or activity in the tumor after its development, we studied Atoh1 dosage and modifications in Shh-type medulloblastoma. Heterozygosity of Atoh1 reduced tumor occurrence and prolonged survival. We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1's transcriptional activity, and is independent of canonical Jak2 signaling. Importantly, inhibition of Jak2 impairs tyrosine 78 phosphorylation and tumor growth in vivo. Taken together, inhibiting Jak2-mediated tyrosine 78 phosphorylation could provide a viable therapy for medulloblastoma.

Article and author information

Author details

  1. Tiemo J Klisch

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    For correspondence
    klisch@bcm.edu
    Competing interests
    No competing interests declared.
    ORCID icon 0000-0001-8182-384X
  2. Anna Vainshtein

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.
  3. Akash J Patel

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.
  4. Huda Y Zoghbi

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    Huda Y Zoghbi, Senior editor, eLife.
    ORCID icon 0000-0002-0700-3349

Funding

Cancer Prevention and Research Institute of Texas (RP110390)

  • Tiemo J Klisch

Howard Hughes Medical Institute

  • Huda Y Zoghbi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures were approved in advance under the guidelines of the Center for Comparative Medicine, Baylor College of Medicine and were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Protocol number AN-5693.

Human subjects: All patients provided written informed consent and tissues were collected under an IRB approved protocol at Baylor College of Medicine (BCM). Protocol number H-35355.

Reviewing Editor

  1. Jeffrey Settleman, Reviewing Editor, Calico Life Sciences, United States

Publication history

  1. Received: September 10, 2017
  2. Accepted: November 22, 2017
  3. Accepted Manuscript published: November 23, 2017 (version 1)
  4. Version of Record published: December 19, 2017 (version 2)

Copyright

© 2017, Klisch et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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