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.

髓母细胞瘤是儿童中最常见的恶性脑肿瘤，其治疗仍然仅限于手术切除，放疗和传统化学疗法。Sonic Hedgehog（Shh）型髓母细胞瘤的长期生存率低至50-60％。我们已经表明，转录因子Atonal同源物1（Atoh1）是小鼠Shh型髓母细胞瘤发展所必需的。为了确定在肿瘤发展后是否降低Atoh1水平或降低肿瘤活性，我们研究了Shh型髓母细胞瘤中Atoh1的剂量和修饰。Atoh1的杂合性减少了肿瘤的发生并延长了生存期。我们发现Atoh1的酪氨酸78仅在肿瘤起始细胞和人SHH型髓母细胞瘤中被Jak2介导的途径磷酸化。酪氨酸78的磷酸化可稳定Atoh1，增加Atoh1' 具有转录活性，并且独立于规范的Jak2信号传导。重要的是，抑制Jak2会削弱酪氨酸78的磷酸化和肿瘤的生长体内。综上所述，抑制Jak2介导的酪氨酸78磷酸化可以为髓母细胞瘤提供可行的治疗方法。