title: Overexpression of IL-3Rα on CD34+CD38- stem cells defines leukemia-initiating cells in Fanconi anemia AML.
abstract: Patients with Fanconi anemia (FA) have a high risk of developing acute myeloid leukemia (AML). In this study, we attempted to identify cell-surface markers for leukemia-initiating cells in FA-AML patients. We found that the IL-3 receptor-α (IL-3Rα) is a promising candidate as an leukemia-initiating cell-specific antigen for FA-AML. Whereas IL-3Rα expression is undetectable on normal CD34(+)CD38(-) HSCs, it is overexpressed on CD34(+)CD38(-) cells from FA patients with AML. We examined the leukemia-initiating cell activity of IL-3Rα-positive FA-AML cells in a "humanized" FA xenotransplant model in which we separated AML cells into IL-3Rα-positive and IL-3Rα-negative CD34 fractions and transplanted them into irradiated recipient mice. In all 3 FA-AML samples, only IL-3Rα-positive cells showed significant levels of engraftment and developed leukemia in the recipient mice. The FA CD34(+)IL-3Rα(+) blasts isolated from leukemic mice exhibited hypersensitivity to IL-3 deprivation and JAK2-STAT5 overactivation after IL-3 treatment. Finally, treatment of FA CD34(+)IL-3Rα(+) blasts with an IL-3Rα-neutralizing antibody inhibited IL-3-mediated proliferation and STAT5 activation. These results demonstrate that IL-3Rα is a cell-surface marker present on FA-AML leukemia-initiating cells and may be a valuable therapeutic target.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. wei.du@cchmc.org
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Xu-E
authors.initials: XE
authors.lastname: Li
authors.forename: Jared
authors.initials: J
authors.lastname: Sipple
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology*; D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology*; D005199:Fanconi Anemia / Q000150:complications* / Q000276:immunology; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D053614:Janus Kinase 2 / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D050799:STAT5 Transcription Factor / Q000276:immunology; D013234:Stem Cells / Q000276:immunology*; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D018952:Antigens, CD34; D053650:Interleukin-3 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2; D051997:ADP-ribosyl Cyclase 1