Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
Elife. 2017 Nov 23;6:e31181. doi: 10.7554/eLife.31181.
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.
治疗儿童最常见的恶性脑瘤——髓母细胞瘤，仍然局限于手术切除、放疗和传统化疗；而 Sonic Hedgehog（Shh）型髓母细胞瘤的长期存活率仅为 50-60%。我们已经表明，转录因子 Atonal homologue 1（Atoh1）在小鼠的 Shh 型髓母细胞瘤发育中是必需的。为了确定在肿瘤发展后降低 Atoh1 的水平或活性是否有益，我们研究了 Shh 型髓母细胞瘤中的 Atoh1 剂量和修饰。Atoh1 的杂合性降低了肿瘤的发生并延长了生存时间。我们发现，Atoh1 的酪氨酸 78 仅在起始细胞和人类 SHH 型髓母细胞瘤中被 Jak2 介导的途径磷酸化。酪氨酸 78 的磷酸化稳定了 Atoh1，增加了 Atoh1 的转录活性，并且不依赖于典型的 Jak2 信号传导。重要的是，抑制 Jak2 会损害体内酪氨酸 78 的磷酸化和肿瘤生长。总之，抑制 Jak2 介导的酪氨酸 78 磷酸化可能为髓母细胞瘤提供可行的治疗方法。
