title: Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia.
abstract: LMO1 is a transcriptional regulator and a T-acute lymphoblastic leukaemia (T-ALL) oncogene. Although first identified in association with a chromosomal translocation in T-ALL, the ectopic expression of LMO1 occurs far more frequently in the absence of any known mutation involving its locus. Given that LMO1 is barely expressed in any haematopoietic lineage, and activation of transcriptional drivers in leukaemic cells is not well described, we investigated the regulation of this gene in normal haematopoietic and leukaemic cells. We show that LMO1 has two promoters that drive reporter gene expression in transgenic mice to neural tissues known to express endogenous LMO1. The LMO1 promoters display bivalent histone marks in multiple blood lineages including T-cells, and a 3' flanking region at LMO1 +57 contains a transcriptional enhancer that is active in developing blood cells in transgenic mouse embryos. The LMO1 promoters become activated in T-ALL together with the 3' enhancer, which is bound in primary T-ALL cells by SCL/TAL1 and GATA3. Taken together, our results show that LMO1 is poised for expression in normal progenitors, where activation of SCL/TAL1 together with a breakdown of epigenetic repression of LMO1 regulatory elements induces ectopic LMO1 expression that contributes to the development and maintenance of T-ALL.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors.forename: S H
authors.initials: SH
authors.lastname: Oram
authors.forename: J
authors.initials: J
authors.lastname: Thoms
authors.forename: J I
authors.initials: JI
authors.lastname: Sive
authors.forename: F J
authors.initials: FJ
authors.lastname: Calero-Nieto
authors.forename: S J
authors.initials: SJ
authors.lastname: Kinston
authors.forename: J
authors.initials: J
authors.lastname: Schütte
authors.forename: K
authors.initials: K
authors.lastname: Knezevic
authors.forename: R B
authors.initials: RB
authors.lastname: Lock
authors.forename: J E
authors.initials: JE
authors.lastname: Pimanda
authors.forename: B
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C065072:LMO1 protein, human; D014157:Transcription Factors