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

Stephen Smith, Rati Tripathi, Charnise Goodings, Susan Cleveland, Elizabeth Mathias, J. Andrew Hardaway, Natalina Elliott, Yajun Yi, Xi Chen, James Downing, Charles Mullighan, Deborah A. Swing, Lino Tessarollo, Qi Li, Paul Love, Nancy A. Jenkins, Neal G. Copeland, Mary Ann Thompson, Yang Du, Utpal P. Davé

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Article numbere85883
JournalPloS one
Volume9
Issue number1
DOIs
StatePublished - Jan 21 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Smith, S., Tripathi, R., Goodings, C., Cleveland, S., Mathias, E., Hardaway, J. A., Elliott, N., Yi, Y., Chen, X., Downing, J., Mullighan, C., Swing, D. A., Tessarollo, L., Li, Q., Love, P., Jenkins, N. A., Copeland, N. G., Thompson, M. A., Du, Y., & Davé, U. P. (2014). LIM Domain Only-2 (LMO2) induces T-cell leukemia by two distinct pathways. PloS one, 9(1), [e85883]. https://doi.org/10.1371/journal.pone.0085883