1] Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA [2] New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
Oncogene. 2014 Jun 19;33(25):3288-97. doi: 10.1038/onc.2013.295. Epub 2013 Aug 5.
Repeated low-dose γ-irradiation (IR) induces thymic lymphoma in mice because of oncogenic mutations propagating from a primitive hematopoietic stem/progenitor cell (HSC) in the bone marrow. It is well known that IR-induced thymic lymphomagenesis is markedly enhanced by p53 deficiency, yet data also indicate that p53-dependent apoptosis can actively drive tumor formation in this model. The latter was recently expounded on by findings from Puma-deficient mice, indicating that loss of this proapoptotic p53 target gene results in protection from IR-induced lymphomagenesis rather than enhanced susceptibility to. Similar to Puma, the transcription factor interferon regulatory factor 5 (Irf5) has been reported as a p53 target gene and is required for DNA damage-induced apoptosis. To date, no studies have been performed to elucidate the in vivo role of IRF5 in tumorigenesis. Given its essential role in DNA damage-induced apoptosis, we explored the tumor suppressor function of IRF5 in IR-induced thymic lymphomagenesis. Somewhat surprisingly, we found that thymic lymphoma development was significantly suppressed in Irf5(-/-) mice as compared with wild-type littermates. Suppression was due, in part, to reduced thymocyte and HSC apoptosis, resulting in reduced compensatory proliferation, and reduced replication stress-associated DNA damage. The observed effects were independent of p53 or Puma as these proteins were upregulated in Irf5(-/-) mice in response to IR. This study demonstrates an important new role for IRF5 in maintaining HSC homeostasis after IR and supports the non-redundant functions of IRF5, p53 and PUMA in DNA damage-induced lymphomagenesis. We propose that IRF5 may be an attractive target for developing therapeutic agents to ameliorate radiation-induced bone marrow injury.
重复低剂量 γ 射线（IR）照射会导致骨髓中的原始造血干细胞/祖细胞（HSC）发生致癌突变，从而在小鼠中诱导胸腺淋巴瘤。众所周知，p53 缺失会显著增强 IR 诱导的胸腺淋巴样瘤发生，但数据也表明 p53 依赖性细胞凋亡可以积极促进该模型中的肿瘤形成。最近，来自 Puma 缺陷小鼠的研究结果阐述了后者，表明丧失这种促凋亡的 p53 靶基因会导致对 IR 诱导的淋巴瘤发生的保护，而不是增强的易感性。与 Puma 相似，转录因子干扰素调节因子 5（Irf5）已被报道为 p53 靶基因，是 DNA 损伤诱导的细胞凋亡所必需的。迄今为止，尚未进行研究阐明 Irf5 在肿瘤发生中的体内作用。鉴于其在 DNA 损伤诱导的细胞凋亡中的重要作用，我们探讨了 Irf5 在 IR 诱导的胸腺淋巴瘤发生中的肿瘤抑制功能。令人惊讶的是，与野生型同窝仔相比，Irf5（-/-）小鼠的胸腺淋巴瘤发育明显受到抑制。抑制部分是由于胸腺细胞和 HSC 凋亡减少，导致代偿性增殖减少，以及与复制应激相关的 DNA 损伤减少。观察到的效应与 p53 或 Puma 无关，因为这些蛋白在 Irf5（-/-）小鼠中对 IR 上调。这项研究表明 Irf5 在 IR 后维持 HSC 稳态方面具有重要的新作用，并支持 Irf5、p53 和 Puma 在 DNA 损伤诱导的淋巴瘤发生中具有非冗余的功能。我们提出，Irf5 可能是开发治疗剂以改善辐射诱导的骨髓损伤的有吸引力的靶标。
