Journal
ONCOGENE
Volume 29, Issue 43, Pages 5796-5808Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.320
Keywords
LMO2; leukaemia; transcriptional regulation; human; ChIP-on-chip; chromatin immunoprecipitation
Funding
- Kay Kendall Leukaemia Fund
- Medical Research Council
- Cancer Research UK
- National Health and Research Council of Australia
- National Institute for Health Research Cambridge Biomedical Research Centre
- Leukaemia and Lymphoma Research UK
- MRC [G0800784, G116/187] Funding Source: UKRI
- Medical Research Council [G0800784B, G116/187, G0800784] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0900729/1] Funding Source: researchfish
Ask authors/readers for more resources
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. Oncogene (2010) 29, 5796-5808; doi: 10.1038/onc.2010.320; published online 2 August 2010
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available