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The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal

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Science  12 Feb 2010:
Vol. 327, Issue 5967, pp. 879-883
DOI: 10.1126/science.1182378

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It's All About Self-Renewal

The Lmo2 oncogene was identified as a contributing factor in human T cell acute lymphoblastic leukemia (T-ALL) nearly two decades ago, but the gene rose to prominence in 2003 when its inadvertent activation by a retroviral vector was shown to cause leukemia in two patients in a gene therapy trial. The cellular mechanism by which the gene product of Lmo2, a transcriptional regulator, induces T-ALL is poorly understood. Studying transgenic mice, McCormack et al. (p. 879, published online 21 January) now show that Lmo2 confers self-renewal activity to committed T cells in the thymus without affecting their capacity for T cell differentiation. These self-renewing cells, which were detectable 8 months prior to the onset of overt leukemia in the mice, expressed genes in common with hematopoietic stem cells (HSCs), suggesting that Lmo2 might reactivate an HSC-specific transcriptional program.

Abstract

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.

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