Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas
Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas
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DOI：
10.1073/pnas.1424104112
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发表时间：
2015-06-23
影响因子：
11.1
通讯作者：
Kappes, Dietmar J.
中科院分区：
文献类型：
--
作者：
Lee, Hyung-Ok;He, Xiao;Kappes, Dietmar J.
转录因子T辅助细胞诱导POZ/Krueppel样因子（ThPOK，由Zbtb 7 b基因编码）在T细胞发育中起着广泛和关键的作用，特别是作为CD 4定型的主要调节因子。在这里，我们表明，小鼠表达组成性T细胞特异性ThPOK转基因（ThPOKconst小鼠）发展胸腺淋巴瘤。这些肿瘤类似于人类T细胞急性淋巴细胞白血病（T-ALL），因为它们主要表现出激活Notch 1突变。如果胸腺细胞发育因重组激活基因（RAG）缺陷而停滞在DN 3期，则淋巴瘤发生被阻止，但通过引入T细胞受体（TCR）转基因或通过向ThPOKconst RAG缺陷小鼠单次注射抗α β TCR抗体而恢复，这促进了向CD 4（+）8（+）（DP）期的发育。因此，TCR信号和/或DN（双阴性）> DP（双阳性）检查点的穿越是ThPOK介导的淋巴瘤发生所需的。这些结果证明了ThPOK、TCR信号传导和淋巴瘤发生之间的新联系。最后，我们提出的证据表明，异位ThPOK表达引起白血病和自我永存DN 4淋巴瘤前体人口。我们的研究结果共同定义了一个新的作用，ThPOK作为一种癌基因，并精确地映射阶段，在胸腺生成敏感的ThPOK依赖性肿瘤的启动。
The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOKconst mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-alpha beta TCR antibody into ThPOKconst RAG-deficient mice, which promotes development to the CD4(+) 8(+) (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.