LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways.

Smith S, Tripathi R, Goodings C, Cleveland S, Mathias E, Hardaway JA, Elliott N, Yi Y, Chen X, Downing J, Mullighan C, Swing DA, Tessarollo L, Li L, Love P, Jenkins NA, Copeland NG, Thompson MA, Du Y, Davé UP
PLoS One. 2014 9 (1): e85883

PMID: 24465765 · PMCID: PMC3897537 · 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.

MeSH Terms (27)

Adaptor Proteins, Signal Transducing Animals Base Sequence Basic Helix-Loop-Helix Transcription Factors Carcinogenesis CD2 Antigens Cell Line, Tumor E-Box Elements Gene Expression Regulation, Leukemic Homeodomain Proteins Humans Leukemia, T-Cell LIM Domain Proteins Mice Mice, Transgenic Molecular Sequence Data Neoplasm Proteins Oncogenes Penetrance Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Promoter Regions, Genetic Protein Binding Proto-Oncogene Proteins Signal Transduction Transcription, Genetic Transcription Factors Up-Regulation

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