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 tumors after their development is beneficial, 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.

中文翻译：

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Jak2 介导的 Atoh1 磷酸化对髓母细胞瘤的生长至关重要

髓母细胞瘤是儿童最常见的恶性脑肿瘤，其治疗仍仅限于手术切除、放疗和传统化疗；Sonic Hedgehog (Shh) 型髓母细胞瘤的长期存活率低至 50-60%。我们已经证明转录因子 Atonal 同源物 1 (Atoh1) 是小鼠 Shh 型髓母细胞瘤发育所必需的。为了确定肿瘤发展后降低 Atoh1 水平或活性是否有益，我们研究了 Atoh1 剂量和 Shh 型髓母细胞瘤中的修饰。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 型成神经管细胞瘤中通过 Jak2 介导的途径磷酸化。酪氨酸 78 的磷酸化稳定 Atoh1，增加 Atoh1 的转录活性，并且独立于规范的 Jak2 信号。重要的是，Jak2 的抑制会损害酪氨酸 78 磷酸化和体内肿瘤生长。总之，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。