1. LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways
- Author
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LiQi Li, Nancy A. Jenkins, Rati Tripathi, Susan M. Cleveland, Deborah A. Swing, Utpal P. Davé, Elizabeth Mathias, Lino Tessarollo, Natalina Elliott, Yajun Yi, Stephen B. Smith, Neal G. Copeland, Mary Ann Thompson, Charles G. Mullighan, Paul E. Love, J. Andrew Hardaway, Charnise Goodings, Xi Chen, James R. Downing, and Yang Du
- Subjects
LMO2 ,Transcription, Genetic ,Mouse ,Carcinogenesis ,T-cell leukemia ,Gene Expression ,lcsh:Medicine ,Penetrance ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,E-Box Elements ,Hematologic Cancers and Related Disorders ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Molecular Cell Biology ,Basic Cancer Research ,Gene expression ,Basic Helix-Loop-Helix Transcription Factors ,Promoter Regions, Genetic ,lcsh:Science ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Gene Expression Regulation, Leukemic ,Animal Models ,Hematology ,LIM Domain Proteins ,Neoplasm Proteins ,Up-Regulation ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Genetic Engineering ,Protein Binding ,Signal Transduction ,Research Article ,Biotechnology ,Leukemia, T-Cell ,Transgene ,Molecular Sequence Data ,CD2 Antigens ,Mice, Transgenic ,Biology ,03 medical and health sciences ,Model Organisms ,LYL1 ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Leukemias ,Animals ,Humans ,Enhancer ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Homeodomain Proteins ,Base Sequence ,Oncogene ,lcsh:R ,Oncogenes ,Hematopoiesis ,Cancer research ,lcsh:Q ,Transcription Factors ,Transgenics - Abstract
The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP-ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2-Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype.
- Published
- 2014