Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2-transgenic mice
Details
Publication Year 2015, Volume 29, Issue #4, Page 927-938
Journal Title
Leukemia
Publication Type
Journal Article
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-) ALL. The primary effect of Lmo2 is to cause self-renewal of developing CD4-CD8- (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.Leukemia accepted article preview online, 06 October 2014. doi:10.1038/leu.2014.292.
Publisher
NPG
WEHI Research Division(s)
Cancer And Haematology
NHMRC Grants
NHMRC/1016647 NHMRC/628386 NHMRC/1003391
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2014-10-13 02:21:54
Last Modified: 2015-12-16 02:38:38
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