Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2-transgenic mice

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.

The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons

“…In various proliferative cell types, a number of genes have been shown to change in expression upon HHEX overexpression or knockdown, including ESM1, VEGF, SST, KIT, and cyclin dependent kinases and associated inhibitors (Noy et al, 2010; Shields et al, 2014; Zhang et al, 2014; Jackson et al, 2015). In the case of ESM1, VEGFR, and SST direct binding of HHEX to promoter sites has been demonstrated, whereas other gene targets may be direct or indirect (Cong et al, 2006; Noy et al, 2010; Zhang et al, 2014).…”

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

“…We took advantage of the mouse model that recapitulates the evolution of the human disease to demonstrate that pre-LSCs are less sensitive than leukemic blasts to drugs that target proliferating cells, such as topoisomerase inhibitors, because of their low proliferative status. Similarly, leukemic blasts and pre-LSCs also exhibit differential sensitivities to radiation (54).…”

Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a

“…Moreover, Hhex is required for the radioresistance of LSCs in a mouse model of human ETP-ALL (Shields et al 2015). However, the role of Hhex in myeloid leukemia has not been studied previously.…”