title: 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.
authors.affiliation: 1] Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Shields
authors.affiliation: 1] Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Alserihi
authors.affiliation: Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Nasa
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bogue
authors.affiliation: 1] Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: W S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: 1] Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: M P
authors.initials: MP
authors.lastname: McCormack
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005720:Gamma Rays; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction; D060168:Thymocytes / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects / Q000637:transplantation; D013950:Thymus Gland / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; D016827:CD8 Antigens; C513080:Hhex protein, mouse; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C513188:Lmo2 protein, mouse; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit