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Evidence for Hox and E2A–PBX1 collaboration in mouse T-cell leukemia

Oncogene volume 27, pages 6356–6364 (2008)Cite this article

Abstract

Using murine Moloney leukemia virus (MMLV)-based proviral insertional mutagenesis, we previously showed a preferential targeting of a small region in the Hoxa gene locus in E2A–PBX1-induced lymphoid leukemia resulting in the overexpression of several Hoxa genes including Hoxa10, Hoxa9 and Hoxa7. This observation suggested a functional interaction between Hox gene overexpression and E2A–PBX1 in lymphoid tumors. To further explore this possibility, we generated a series of compound E2A–PBX1 × Hox transgenic mice and tested the genetic interaction between these genes in the generation of lymphoid leukemia in vivo. Results presented in this report show that the onset of T-cell leukemia is significantly accelerated in E2A–PBX1 × Hoxb4 compound transgenic animals when compared with control E2A–PBX1 or Hoxb4 littermates. Hoxa9 appears less potent than Hoxb4 to accelerate E2A–PBX1-induced T-cell leukemia in mice. E2A–PBX1-induced T-cell leukemias express much higher levels of Hoxa genes than MMLV-induced counterparts, possibly suggesting a contribution of these genes to T-cell transformation by E2A–PBX1. Collectively, these data provide the first genetic evidence showing oncogenic collaboration between E2A–PBX1 and a Hox gene in lymphoid malignancies in vivo and document the specific deregulation of a subgroup of Hoxa genes in these leukemias.

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Acknowledgements

We thank Melanie Frechette for assistance with the animal care and transplantation experiments, and to the personnel from the transgenic animal facility at the Institute for Clinical Research of Montreal (IRCM) for the generation of Hoxb4 and Hoxa9 transgenic lines. We also thank Eric Massicotte and Martine Dupuis from the flow cytometry service of IRCM, and Danielle Gagné from the flow cytometry service of IRIC for assistance in FACS analysis. Dr Alex Thompson (Queen's University, Belfast, UK) is thanked for critically reading the manuscript. This work was supported by funds from the Canadian Cancer Society through a NCIC grant to GS (no. 018478) and the Canada Research Chair program also to GS.

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Authors and Affiliations

  1. Laboratory of Molecular Genetics of Hematopoietic Stem Cells, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec, Canada

    J Bijl, J Krosl, N Mayotte & G Sauvageau

  2. Division of Hematology, Research Center of the Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada

    J Bijl, C-E Lebert-Ghali & G Sauvageau

  3. Department of Medicine, Université de Montréal, Montréal, Quebec, Canada

    J Bijl & G Sauvageau

  4. Section of Cellular Interactions and Development, Clinical Research Institute of Montreal, Montréal, Quebec, Canada

    J Vacher

  5. Leukemia Cell Bank of Québec, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada

    G Sauvageau

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  1. J Bijl
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Correspondence to J Bijl.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Bijl, J., Krosl, J., Lebert-Ghali, CE. et al. Evidence for Hox and E2A–PBX1 collaboration in mouse T-cell leukemia. Oncogene 27, 6356–6364 (2008). https://doi.org/10.1038/onc.2008.233

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