AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model
AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model
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DOI：
10.1038/leu.2010.40
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发表时间：
2010-05-01
期刊：
影响因子：
11.4
通讯作者：
Kitamura, T.
中科院分区：
文献类型：
--
作者：
Komeno, Y.;Kitaura, J.;Kitamura, T.
激活诱导的胞苷脱氨酶 (AID) 通过体细胞超突变 (SHM) 和类别转换重组 (CSR) 使免疫球蛋白多样化。 AID 转基因小鼠患上 T 淋巴瘤，表明 AID 的组成型表达会导致肿瘤发生。在这里，我们移植了用 AID 转导的小鼠骨髓细胞。 32 只受体小鼠中有 24 只在移植后 2-4 个月出现 T 淋巴瘤。令人惊讶的是，与 AID 转基因小鼠不同，7 名接受者患上 B 白血病/淋巴瘤的潜伏期更长。没有一只小鼠患有骨髓性白血病。当我们使用裸鼠作为受体时，它们仅患上 B 型白血病/淋巴瘤，大概是由于缺乏胸腺。 AID突变体的分析表明，为了使AID具有最大的诱导淋巴瘤的能力，需要具有SHM活性的完整形式。除了一例出现 K-ras 活性突变体外，在 T 淋巴瘤中无法鉴定出特异性突变；然而，Notch1 在大多数情况下被组成型激活。重要的是，在 B 白血病/淋巴瘤中观察到 Ebf1 或 Pax5 的截短。总之，这是第一份关于 AID 过度表达在小鼠模型中促进 B 细胞淋巴瘤发生的潜力的报告。骨髓细胞中 AID 的异常表达主要通过其作为突变子的功能，以细胞谱系依赖性方式诱导白血病/淋巴瘤。白血病 (2010) 24, 1018-1024; doi：10.1038/leu.2010.40； 2010 年 4 月 1 日在线发布
Activation-induced cytidine deaminase (AID) diversifies immunoglobulin through somatic hypermutation (SHM) and class-switch recombination (CSR). AID-transgenic mice develop T-lymphoma, indicating that constitutive expression of AID leads to tumorigenesis. Here, we transplanted mouse bone marrow cells transduced with AID. Twenty-four of the 32 recipient mice developed T-lymphoma 2-4 months after the transplantation. Surprisingly, unlike AID-transgenic mice, seven recipients developed B-leukemia/lymphoma with longer latencies. None of the mice suffered from myeloid leukemia. When we used nude mice as recipients, they developed only B-leukemia/lymphoma, presumably due to lack of thymus. Analysis of AID mutants suggested that an intact form with SHM activity is required for maximum ability of AID to induce lymphoma. Except for a K-ras active mutant in one case, specific mutations could not be identified in T-lymphoma; however, Notch1 was constitutively activated in most cases. Importantly, truncations of Ebf1 or Pax5 were observed in B-leukemia/lymphoma. In conclusion, this is the first report on the potential of AID overexpression to promote B-cell lymphomagenesis in a mouse model. Aberrant expression of AID in bone marrow cells induced leukemia/lymphoma in a cell-lineage-dependent manner, mainly through its function as a mutator. Leukemia (2010) 24, 1018-1024; doi:10.1038/leu.2010.40; published online 1 April 2010