The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal
The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal
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DOI：
10.1126/science.1182378
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发表时间：
2010-02-12
期刊：
影响因子：
56.9
通讯作者：
Curtis, David J.
中科院分区：
文献类型：
--
作者：
McCormack, Matthew P.;Young, Lauren F.;Curtis, David J.
LMO 2致癌基因导致一个人类T细胞急性淋巴细胞白血病（T-ALL）的子集，包括四例在基因治疗试验中出现的不良事件。为了研究LMO 2诱导的白血病的细胞起源，我们使用细胞命运图来研究LMO 2基因在胸腺中组成型表达的小鼠。Lmo 2在明显的T-ALL发展之前8个多月诱导小鼠中定型T细胞的自我更新。这些自我更新的细胞保留了T细胞分化的能力，但表达了造血干细胞（HSC）的几个典型基因，这表明Lmo 2可能会重新激活HSC特异性转录程序。一个这样的基因，Hhex的强制表达，足以启动胸腺细胞在体内的自我更新。因此，Lmo 2促进白血病前胸腺细胞的自我更新，提供了一种机制，通过这种机制，定型T细胞可以积累白血病转化所需的额外基因突变。
The LMO2 oncogene causes a subset of human T cell acute lymphoblastic leukemias (T-ALL), including four cases that arose as adverse events in gene therapy trials. To investigate the cellular origin of LMO2-induced leukemia, we used cell fate mapping to study mice in which the Lmo2 gene was constitutively expressed in the thymus. Lmo2 induced self-renewal of committed T cells in the mice more than 8 months before the development of overt T-ALL. These self-renewing cells retained the capacity for T cell differentiation but expressed several genes typical of hematopoietic stem cells (HSCs), suggesting that Lmo2 might reactivate an HSC-specific transcriptional program. Forced expression of one such gene, Hhex, was sufficient to initiate self-renewal of thymocytes in vivo. Thus, Lmo2 promotes the self-renewal of preleukemic thymocytes, providing a mechanism by which committed T cells can then accumulate additional genetic mutations required for leukemic transformation.