The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal
- Author(s)
- McCormack, MP; Young, LF; Vasudevan, S; de Graaf, CA; Codrington, R; Rabbitts, TH; Jane, SM; Curtis, DJ;
- Details
- Publication Year 2010-02-12,Volume 327,Issue #5967,Page 879-883
- Journal Title
- SCIENCE
- Publication Type
- Journal Article
- 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.
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE
- Keywords
- ACUTE LYMPHOBLASTIC-LEUKEMIA; T-CELL LEUKEMIA; GENE-THERAPY; CHROMOSOMAL TRANSLOCATIONS; RETROVIRAL INSERTION; PROTEIN RBTN2; SCID-X1; HEMATOPOIESIS; TRANSCRIPTION; ACTIVATION
- Publisher's Version
- https://doi.org/10.1126/science.1182378
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2010-02-12 12:00:00