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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.

Original publication




Journal article



Publication Date





879 - 883


Adaptor Proteins, Signal Transducing, Animals, Cell Differentiation, Cell Transformation, Neoplastic, DNA-Binding Proteins, Down-Regulation, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Homeodomain Proteins, Humans, LIM Domain Proteins, Metalloproteins, Mice, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, Oncogenes, Precursor Cells, T-Lymphoid, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Preleukemia, Proto-Oncogene Proteins, T-Lymphocyte Subsets, T-Lymphocytes, Thymus Gland, Transcription Factors, Transcription, Genetic, Up-Regulation