Oncogenic Runx1-Myc axis in p53-deficient thymic lymphoma
Oncogenic Runx1-Myc axis in p53-deficient thymic lymphoma
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DOI：
10.1016/j.gene.2022.146234
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发表时间：
2022-02-04
期刊：
影响因子：
3.5
通讯作者：
Ito，Kosei
中科院分区：
文献类型：
--
作者：
Date，Yuki;Taniuchi，Ichiro;Ito，Kosei
p53 缺陷和 Mycdys 调节通常与癌症相关。然而，人们对这两个主要致癌事件之间的分子机制知之甚少。使用由 p53 丢失引起的骨肉瘤模型，我们最近发现 Runx3 通过 mR1（Myc 启动子中的 Runx 共有位点）异常上调 Myc。在这里，我们关注胸腺淋巴瘤（一种由小鼠种系 p53 缺失引起的主要肿瘤类型），并检查致癌 Runx-Myc 轴是否在 p53 缺陷型淋巴瘤的发展中发挥显着作用。胸腺细胞中特别缺乏p53的小鼠（LP小鼠）大多死于胸腺淋巴瘤。与正常胸腺相比，Runx1 和 Myc 在 LP 小鼠淋巴瘤中表达上调。 Runx1 或 Myc 的缺失可延长 LP 小鼠的寿命并抑制淋巴瘤的发展。在从 LP 小鼠中分离出的淋巴瘤细胞中，Runx1 的敲低导致 Myc 抑制，从而削弱了它们在免疫功能低下小鼠中的肿瘤形成能力。 Runx1 和 H3K27ac（一种活性染色质标记）均富集了 mR1 位点。携带 mR1 突变的 LP 小鼠寿命更长，淋巴瘤发病率更低。使用 Runx 抑制剂 AI-10-104 进行治疗可提高 LP 小鼠的存活率。这些结果表明 Runx1 上调 Myc 是 p53 缺陷型胸腺淋巴瘤发展的关键事件，并为针对 p53 缺陷型恶性肿瘤中的 Runx 家族提供了临床依据。
p53deficiency andMycdysregulation are frequently associated with cancer. However, the molecular mechanisms linking these two major oncogenic events are poorly understood. Using an osteosarcoma model caused by p53 loss, we have recently shown that Runx3 aberrantly upregulates Myc via mR1, a Runx consensus site in theMycpromoter. Here, we focus on thymic lymphoma, a major tumour type caused by germline p53 deletion in mice, and examine whether the oncogenic Runx–Myc axis plays a notable role in the development ofp53-deficient lymphoma. Mice lackingp53specifically in thymocytes (LP mice) mostly succumbed to thymic lymphoma. Runx1 and Myc were upregulated in LP mouse lymphoma compared with the normal thymus. Depletion of Runx1 or Myc prolonged the lifespan of LP mice and suppressed lymphoma development. In lymphoma cells isolated from LP mice, knockdown of Runx1 led to Myc suppression, weakening their tumour forming ability in immunocompromised mice. The mR1 locus was enriched by both Runx1 and H3K27ac, an active chromatin marker. LP mice with mutated mR1 had a longer lifespan and a lower incidence of lymphoma. Treatment with AI-10-104, a Runx inhibitor, improved the survival of LP mice. These results suggest that Myc upregulation by Runx1 is a key event inp53-deficient thymic lymphoma development and provide a clinical rationale for targeting the Runx family inp53-deficient malignancies.