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HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias

The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in...

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Autores principales: Calero-Nieto, F J, Joshi, A, Bonadies, N, Kinston, S, Chan, W-I, Gudgin, E, Pridans, C, Landry, J-R, Kikuchi, J, Huntly, B J, Gottgens, B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898495/
https://www.ncbi.nlm.nih.gov/pubmed/23708655
http://dx.doi.org/10.1038/onc.2013.175
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author Calero-Nieto, F J
Joshi, A
Bonadies, N
Kinston, S
Chan, W-I
Gudgin, E
Pridans, C
Landry, J-R
Kikuchi, J
Huntly, B J
Gottgens, B
author_facet Calero-Nieto, F J
Joshi, A
Bonadies, N
Kinston, S
Chan, W-I
Gudgin, E
Pridans, C
Landry, J-R
Kikuchi, J
Huntly, B J
Gottgens, B
author_sort Calero-Nieto, F J
collection PubMed
description The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.
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spelling pubmed-38984952014-01-24 HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias Calero-Nieto, F J Joshi, A Bonadies, N Kinston, S Chan, W-I Gudgin, E Pridans, C Landry, J-R Kikuchi, J Huntly, B J Gottgens, B Oncogene Original Article The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2. Nature Publishing Group 2013-11-28 2013-05-27 /pmc/articles/PMC3898495/ /pubmed/23708655 http://dx.doi.org/10.1038/onc.2013.175 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
Calero-Nieto, F J
Joshi, A
Bonadies, N
Kinston, S
Chan, W-I
Gudgin, E
Pridans, C
Landry, J-R
Kikuchi, J
Huntly, B J
Gottgens, B
HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias
title HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias
title_full HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias
title_fullStr HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias
title_full_unstemmed HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias
title_short HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias
title_sort hox-mediated lmo2 expression in embryonic mesoderm is recapitulated in acute leukaemias
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898495/
https://www.ncbi.nlm.nih.gov/pubmed/23708655
http://dx.doi.org/10.1038/onc.2013.175
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