Introduction: 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.
Methods: We used a combination of mouse genetics, protein mass spectrometry, in vitro cell culture studies as well as in vivo flank xenografts to study the relation of Jak2 and Atoh1.
Results: 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.
Conclusions: We conclude that inhibiting Jak2-mediated tyrosine 78 phosphorylation could provide a viable therapy for medulloblastoma.
Patient Care: The study and understanding of the underpinnings of medulloblastoma will lead to better targeted, less invasive patient care in the future.
Learning Objectives: 1) Atoh1 is critical for medulloblastoma growths.
2) Jak Signaling is a novel pathway in medulloblastoma.
3) Targeting multiple signaling pathways will benefit patients with medulloblastoma.
References: Klisch TJ, Vainshtein A, Patel A, Zoghbi HY. (2017) Medulloblastoma growth is dependent on Jak2-mediated phosphorylation of Atoh1. eLife 6