LIM Domain Only-2 (LMO2) Induces T-Cell Leukemia by Two Distinct Pathways

• Published in: PloS one Vol. 9; no. 1; p. e85883
• Main Authors: Smith, Stephen, Tripathi, Rati, Goodings, Charnise, Cleveland, Susan, Mathias, Elizabeth, Hardaway, J. Andrew, Elliott, Natalina, Yi, Yajun, Chen, Xi, Downing, James, Mullighan, Charles, Swing, Deborah A., Tessarollo, Lino, Li, Liqi, Love, Paul, Jenkins, Nancy A., Copeland, Neal G., Thompson, Mary Ann, Du, Yang, Davé, Utpal P.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.01.2014; Public Library of Science (PLoS)
• Subjects: Activation; Acute lymphoblastic leukemia; Adaptor Proteins, Signal Transducing - metabolism; Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biology; Cancer; Carcinogenesis - metabolism; Carcinogenesis - pathology; CD2 Antigens - metabolism; Cell Line, Tumor; Children & youth; Childrens health; Clustering; Deactivation; Deregulation; E-Box Elements - genetics; Gene expression; Gene Expression Regulation, Leukemic; Gene therapy; Genes; Genetic aspects; Genetic engineering; Genomes; Hematology; Homeodomain Proteins - genetics; Hospitals; Humans; Inactivation; Leukemia; Leukemia, T-Cell - genetics; Leukemia, T-Cell - metabolism; Leukemia, T-Cell - pathology; LIM Domain Proteins - metabolism; Lymphocytes; Lymphocytes T; Medicine; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; Neoplasm Proteins - metabolism; Notch1 protein; Oncogenes; Oncology; Pathology; Penetrance; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Promoter Regions, Genetic - genetics; Protein Binding; Proteins; Proto-Oncogene Proteins - metabolism; RNA polymerase; Rodents; Signal Transduction; T cells; Transcription; Transcription (Genetics); Transcription factors; Transcription Factors - genetics; Transcription, Genetic; Transgenic animals; Transgenic mice; Up-Regulation - genetics; Vectors (Biology); United States > US; Maryland; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0085883

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.