Overexpression of IL-3Rα on CD34+CD38- stem cells defines leukemia-initiating cells in Fanconi anemia AML

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-alpha (IL-3R alpha) is a promising candidate as an leukemia-initiating cell-specific antigen for FA-AML. Whereas IL-3R alpha 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-3R alpha-positive FA-AML cells in a humanized FA xenotransplant model in which we separated AML cells into IL-3R alpha-positive and IL-3R alpha-negative CD34 fractions and transplanted them into irradiated recipient mice. In all 3 FA-AML samples, only IL-3R alpha-positive cells showed significant levels of engraftment and developed leukemia in the recipient mice. The FACD34(+)IL-3R alpha(+)blasts isolated from leukemic mice exhibited hypersensitivity to IL-3 deprivation and JAK2-STAT5 overactivation after IL-3 treatment. Finally, treatment of FACD34(+)IL-3R alpha(+)blasts with an IL-3R alpha-neutralizing antibody inhibited IL-3-mediated proliferation and STAT5 activation. These results demonstrate that IL-3R alpha is a cell-surface marker present on FA-AML leukemia-initiating cells and may be a valuable therapeutic target. (Blood. 2011;117(16):4243-4252)