Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors

Josette Reneé Landry, Nicolas Bonadies, Sarah Kinston, Kathy Knezevic, Nicola K. Wilson, S. Helen Oram, Mary Janes, Sandra Piltz, Michelle Hammett, Jacinta Carter, Tina Hamilton, Ian J. Donaldson, Georges Lacaud, Jonathan Frampton, George Follows, Valerie Kouskoff, Berthold Göttgens

Research output: Contribution to journalArticle

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Abstract

The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodefi-ciency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks.

LanguageEnglish
Pages5783-5792
Number of pages10
JournalBlood
Volume113
Issue number23
DOIs
Publication statusPublished - 18 Nov 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Landry, Josette Reneé ; Bonadies, Nicolas ; Kinston, Sarah ; Knezevic, Kathy ; Wilson, Nicola K. ; Oram, S. Helen ; Janes, Mary ; Piltz, Sandra ; Hammett, Michelle ; Carter, Jacinta ; Hamilton, Tina ; Donaldson, Ian J. ; Lacaud, Georges ; Frampton, Jonathan ; Follows, George ; Kouskoff, Valerie ; Göttgens, Berthold. / Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. In: Blood. 2009 ; Vol. 113, No. 23. pp. 5783-5792.
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title = "Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors",
abstract = "The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodefi-ciency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks.",
author = "Landry, {Josette Rene{\'e}} and Nicolas Bonadies and Sarah Kinston and Kathy Knezevic and Wilson, {Nicola K.} and Oram, {S. Helen} and Mary Janes and Sandra Piltz and Michelle Hammett and Jacinta Carter and Tina Hamilton and Donaldson, {Ian J.} and Georges Lacaud and Jonathan Frampton and George Follows and Valerie Kouskoff and Berthold G{\"o}ttgens",
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Landry, JR, Bonadies, N, Kinston, S, Knezevic, K, Wilson, NK, Oram, SH, Janes, M, Piltz, S, Hammett, M, Carter, J, Hamilton, T, Donaldson, IJ, Lacaud, G, Frampton, J, Follows, G, Kouskoff, V & Göttgens, B 2009, 'Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors', Blood, vol. 113, no. 23, pp. 5783-5792. https://doi.org/10.1182/blood-2008-11-187757

Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. / Landry, Josette Reneé; Bonadies, Nicolas; Kinston, Sarah; Knezevic, Kathy; Wilson, Nicola K.; Oram, S. Helen; Janes, Mary; Piltz, Sandra; Hammett, Michelle; Carter, Jacinta; Hamilton, Tina; Donaldson, Ian J.; Lacaud, Georges; Frampton, Jonathan; Follows, George; Kouskoff, Valerie; Göttgens, Berthold.

In: Blood, Vol. 113, No. 23, 18.11.2009, p. 5783-5792.

Research output: Contribution to journalArticle

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T1 - Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors

AU - Landry, Josette Reneé

AU - Bonadies, Nicolas

AU - Kinston, Sarah

AU - Knezevic, Kathy

AU - Wilson, Nicola K.

AU - Oram, S. Helen

AU - Janes, Mary

AU - Piltz, Sandra

AU - Hammett, Michelle

AU - Carter, Jacinta

AU - Hamilton, Tina

AU - Donaldson, Ian J.

AU - Lacaud, Georges

AU - Frampton, Jonathan

AU - Follows, George

AU - Kouskoff, Valerie

AU - Göttgens, Berthold

PY - 2009/11/18

Y1 - 2009/11/18

N2 - The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodefi-ciency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks.

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