Abstract
Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute leukemias, in particular poor prognosis early T-cell precursor-like (ETP-) acute lymphoblastic leukemia (ALL). The primary effect of Lmo2 is to cause self-renewal of developing CD4−CD8− (double negative, DN) T cells in the thymus, leading to serially transplantable thymocytes that eventually give rise to leukemia. These self-renewing thymocytes are intrinsically radioresistant implying that they may be a source of leukemia relapse after therapy. The homeobox transcription factor, Hhex, is highly upregulated in Lmo2-transgenic thymocytes and can phenocopy Lmo2 in inducing thymocyte self-renewal, implying that Hhex may be a key component of the Lmo2-induced self-renewal program. To test this, we conditionally deleted Hhex in the thymi of Lmo2-transgenic mice. Surprisingly, this did not prevent accumulation of DN thymocytes, nor alter the rate of overt leukemia development. However, deletion of Hhex abolished the transplantation capacity of Lmo2-transgenic thymocytes and overcame their radioresistance. We found that Hhex regulates Kit expression in Lmo2-transgenic thymocytes and that abrogation of Kit signaling phenocopied loss of Hhex in abolishing the transplantation capacity and radioresistance of these cells. Thus, targeting the Kit signaling pathway may facilitate the eradication of leukemia-initiating cells in immature T-cell leukemias in which it is expressed.
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Acknowledgements
We thank WEHI Bioservices for animal husbandry, Prof. Doug Hilton for providing the KitWv mice, Hesham Abdulla for technical assistance and Prof. Richard Lock and Dr Seong-Lin Khaw for discussions. This work was supported by a Program Grant (1016647 to WSA), Project Grants (628386 and 1003391 to MPM), Fellowship (1058344 to WSA) and an Independent Research Institute Infrastructure Support (IRIIS) Scheme from the Australian National Health and Medical Research Council (NHMRC), grants-in-aid from the Cancer Council of Victoria and the Leukemia Foundation of Australia (MPM), a Future Fellowship from the Australian Research Council (MPM), the Australian Cancer Research Foundation and a Victorian State Government Operational Infrastructure Grant.
Author Contributions
MPM and BJS designed research, performed research, analyzed data and wrote the manuscript; CN and RA performed research and analyzed data; CWB designed research and provided critical reagents. WSA designed research, analyzed data and wrote the manuscript.
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Shields, B., Alserihi, R., Nasa, C. et al. Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2-transgenic mice. Leukemia 29, 927–938 (2015). https://doi.org/10.1038/leu.2014.292
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DOI: https://doi.org/10.1038/leu.2014.292
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