LIM Domain Only-2 (LMO2) induces T-cell leukemia by two distinct pathways

Academic Article

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. © 2014 Smith et al.
  • Published In

  • PLoS ONE  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 26956626
  • Author List

  • Smith S; Tripathi R; Goodings C; Cleveland S; Mathias E; Hardaway JA; Elliott N; Yi Y; Chen X; Downing J
  • Volume

  • 9
  • Issue

  • 1