Portal de Periódicos da CAPES

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

2010; American Association for the Advancement of Science; Volume: 327; Issue: 5967 Linguagem: Inglês

10.1126/science.1182378

1095-9203

Matthew P. McCormack, Lauren Young, Sumitha Vasudevan, Carolyn A. de Graaf, Rosalind Codrington, Terence H. Rabbitts, Stephen M. Jane, David J. Curtis,

Acute Lymphoblastic Leukemia research

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.