A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

Oncogene. 2010 Oct 28;29(43):5796-808. doi: 10.1038/onc.2010.320. Epub 2010 Aug 2.

Abstract

The T-cell oncogene Lim-only 2 (LMO2) critically influences both normal and malignant haematopoiesis. LMO2 is not normally expressed in T cells, yet ectopic expression is seen in the majority of T-acute lymphoblastic leukaemia (T-ALL) patients with specific translocations involving LMO2 in only a subset of these patients. Ectopic lmo2 expression in thymocytes of transgenic mice causes T-ALL, and retroviral vector integration into the LMO2 locus was implicated in the development of clonal T-cell disease in patients undergoing gene therapy. Using array-based chromatin immunoprecipitation, we now demonstrate that in contrast to B-acute lymphoblastic leukaemia, human T-ALL samples largely use promoter elements with little influence from distal enhancers. Active LMO2 promoter elements in T-ALL included a previously unrecognized third promoter, which we demonstrate to be active in cell lines, primary T-ALL patients and transgenic mice. The ETS factors ERG and FLI1 previously implicated in lmo2-dependent mouse models of T-ALL bind to the novel LMO2 promoter in human T-ALL samples, while in return LMO2 binds to blood stem/progenitor enhancers in the FLI1 and ERG gene loci. Moreover, LMO2, ERG and FLI1 all regulate the +1 enhancer of HHEX/PRH, which was recently implicated as a key mediator of early progenitor expansion in LMO2-driven T-ALL. Our data therefore suggest that a self-sustaining triad of LMO2/ERG/FLI1 stabilizes the expression of important mediators of the leukaemic phenotype such as HHEX/PRH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / genetics*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic / genetics*
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics
  • Humans
  • LIM Domain Proteins
  • Metalloproteins / genetics*
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Promoter Regions, Genetic / genetics*
  • Proto-Oncogene Protein c-fli-1 / genetics
  • Proto-Oncogene Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators / genetics
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription, Genetic
  • Transcriptional Regulator ERG

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • ERG protein, human
  • FLI1 protein, human
  • HHEX protein, human
  • Homeodomain Proteins
  • LIM Domain Proteins
  • LMO2 protein, human
  • Metalloproteins
  • Proto-Oncogene Protein c-fli-1
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Regulator ERG