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.
Highlights
Lim-only 1 (LMO1) known as T-cell translocation gene 1 (TTG-1) and Rhombotin 1 (RBTN-1) encodes a LIM domain transcriptional cofactor, and was originally identified at a chromosomal breakpoint in a T-acute lymphoblastic leukaemia (T-ALL) cell line bearing the t(11;14)(p15;q11) translocation.[1,2] LMO1 is not normally expressed in T-cells, but the t(11;14)(p15;q11) juxtaposes LMO1 to gene regulatory elements within the T-cell receptor a/d loci leading to ectopic expression in a T-lymphoid environment
Given that LMO1 expression is minimal in normal blood cells but can be substantial in a subset of T-ALL leukaemia patients, we investigated whether the LMO1 promoters and þ 57 enhancer element showed activity in T-ALL cells
The early paradigm for this mode of leukaemia oncogene function was provided by analysis of the t(8;14) translocation in Burkitt’s lymphoma that results in the ectopic expression of C-MYC.[38]
Summary
Lim-only 1 (LMO1) known as T-cell translocation gene 1 (TTG-1) and Rhombotin 1 (RBTN-1) encodes a LIM domain transcriptional cofactor, and was originally identified at a chromosomal breakpoint in a T-acute lymphoblastic leukaemia (T-ALL) cell line bearing the t(11;14)(p15;q11) translocation.[1,2] LMO1 is not normally expressed in T-cells, but the t(11;14)(p15;q11) juxtaposes LMO1 to gene regulatory elements within the T-cell receptor a/d loci leading to ectopic expression in a T-lymphoid environment. Given the unequivocal demonstration through transgenic mouse experiments that ectopic LMO1 expression in T-cells causes T-ALL,[4] a detailed understanding of transcriptional control mechanisms operating at the LMO1 gene locus would appear vital to elucidate the mechanisms responsible for ectopic expression in T-ALL patients without LMO1 translocations. LMO1 forms multiprotein complexes with transcriptional regulators such as SCL,[8,9] LDB1,10 GATA3.11
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