Division of Experimental Hematology, Department of Hematology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Blood. 2011 May 19;117(20):5453-62. doi: 10.1182/blood-2010-09-309831. Epub 2011 Mar 22.
LMO2 is a target of chromosomal translocations in T-cell tumors and was activated by retroviral vector insertions in T-cell tumors from X-SCID patients in gene therapy trials. To better understand the cooperating genetic events in LMO2-associated T-cell acute lymphoblastic leukemia (T-ALL), we investigated the roles of Arf tumor suppressor loss and Notch activation in murine models of transplantation. Lmo2 overexpression enhanced the expansion of primitive DN2 thymocytes, eventually facilitating the stochastic induction of clonal CD4(+)/CD8(+) malignancies. Inactivation of the Arf tumor suppressor further increased the self-renewal capacity of the primitive, preleukemic thymocyte pool and accelerated the development of aggressive, Lmo2-induced T-cell lympholeukemias. Notch mutations were frequently detected in these Lmo2-induced tumors. The Arf promoter was not directly engaged by Lmo2 or mutant Notch, and use of a mouse model in which activation of a mutant Notch allele depends on previous engagement of the Arf promoter revealed that Notch activation could occur as a subsequent event in T-cell tumorigenesis. Therefore, Lmo2 cooperates with Arf loss to enhance self-renewal in primitive thymocytes. Notch mutation and Arf inactivation appear to independently cooperate in no requisite order with Lmo2 overexpression in inducing T-ALL, and all 3 events remained insufficient to guarantee immediate tumor development.
LMO2 是 T 细胞肿瘤中染色体易位的靶标，并且在 X-SCID 患者的基因治疗试验中的 T 细胞肿瘤中通过逆转录病毒载体插入而被激活。为了更好地理解 LMO2 相关 T 细胞急性淋巴细胞白血病（T-ALL）中合作的遗传事件，我们在移植小鼠模型中研究了 Arf 肿瘤抑制基因缺失和 Notch 激活的作用。Lmo2 的过表达增强了原始 DN2 胸腺细胞的扩增，最终促进了克隆性 CD4(+)/CD8(+)恶性肿瘤的随机诱导。Arf 肿瘤抑制基因的失活进一步增加了原始、白血病前期胸腺细胞池的自我更新能力，并加速了侵袭性、由 Lmo2 诱导的 T 细胞淋巴白血病的发展。在这些由 Lmo2 诱导的肿瘤中经常检测到 Notch 突变。Arf 启动子未被 Lmo2 或突变型 Notch 直接结合，并且使用一种依赖于 Arf 启动子先前结合来激活突变型 Notch 等位基因的小鼠模型表明 Notch 激活可能作为 T 细胞肿瘤发生的后续事件发生。因此，Lmo2 与 Arf 缺失合作以增强原始胸腺细胞中的自我更新。 Notch 突变和 Arf 失活似乎与 Lmo2 过表达独立地合作，在诱导 T-ALL 中不需要特定的顺序，并且所有 3 个事件仍然不足以保证立即发生肿瘤发展。
