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Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia

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 th...

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Autores principales: Oram, S H, Thoms, J, Sive, J I, Calero-Nieto, F J, Kinston, S J, Schütte, J, Knezevic, K, Lock, R B, Pimanda, J E, Göttgens, B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677138/
https://www.ncbi.nlm.nih.gov/pubmed/23302769
http://dx.doi.org/10.1038/leu.2013.2
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author Oram, S H
Thoms, J
Sive, J I
Calero-Nieto, F J
Kinston, S J
Schütte, J
Knezevic, K
Lock, R B
Pimanda, J E
Göttgens, B
author_facet Oram, S H
Thoms, J
Sive, J I
Calero-Nieto, F J
Kinston, S J
Schütte, J
Knezevic, K
Lock, R B
Pimanda, J E
Göttgens, B
author_sort Oram, S H
collection PubMed
description 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.
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spelling pubmed-36771382013-06-10 Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia Oram, S H Thoms, J Sive, J I Calero-Nieto, F J Kinston, S J Schütte, J Knezevic, K Lock, R B Pimanda, J E Göttgens, B Leukemia Original Article 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. Nature Publishing Group 2013-06 2013-02-01 /pmc/articles/PMC3677138/ /pubmed/23302769 http://dx.doi.org/10.1038/leu.2013.2 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by/3.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/
spellingShingle Original Article
Oram, S H
Thoms, J
Sive, J I
Calero-Nieto, F J
Kinston, S J
Schütte, J
Knezevic, K
Lock, R B
Pimanda, J E
Göttgens, B
Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia
title Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia
title_full Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia
title_fullStr Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia
title_full_unstemmed Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia
title_short Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia
title_sort bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene lmo1 for ectopic expression in t-cell leukaemia
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677138/
https://www.ncbi.nlm.nih.gov/pubmed/23302769
http://dx.doi.org/10.1038/leu.2013.2
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