Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth

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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.

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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.

"This ORCID iD identifies the author of this article:" 0000-0001-8182-384X
Anna Vainshtein

Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States

Competing interests
No competing interests declared.
Akash J Patel

Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States

Competing interests
No competing interests declared.
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.

"This ORCID iD identifies the author of this article:" 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.

Copyright

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.