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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Cell Differentiation
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Cell Transformation, Neoplastic / genetics*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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Homeodomain Proteins / genetics
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Humans
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LIM Domain Proteins
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Metalloproteins / genetics*
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Metalloproteins / metabolism
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Mice
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Mice, Transgenic
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Oligonucleotide Array Sequence Analysis
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Oncogenes*
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Precursor Cells, T-Lymphoid / physiology*
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Precursor Cells, T-Lymphoid / transplantation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Preleukemia / genetics
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Preleukemia / metabolism
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Preleukemia / pathology
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Proto-Oncogene Proteins
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T-Lymphocyte Subsets
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T-Lymphocytes / physiology*
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T-Lymphocytes / transplantation
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Thymus Gland / metabolism
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Thymus Gland / pathology
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Transcription Factors / genetics
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Transcription, Genetic
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Up-Regulation
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Hhex protein, mouse
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Homeodomain Proteins
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LIM Domain Proteins
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LMO2 protein, human
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Lmo2 protein, mouse
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Metalloproteins
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Proto-Oncogene Proteins
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Transcription Factors