Overexpression of IL-3R alpha on CD34+CD38- Stem Cells Defines Leukemia-Initiating Cells In FA AML.

Abstract 1667

Patients with Fanconi anemia (FA) have high risk of developing acute myeloid leukemia (AML). In this study, we attempted to identify cell surface markers for leukemia-initiating cells (LICs) in FA AML patients. We found that interleukin-3 receptor alpha (IL-3R alpha) is a promising candidate as an LIC-specific antigen for FA AML. While IL-3R alpha expression is undetectable on normal CD34⁺CD38^- hematopoietic stem cells (HSCs), it is overexpressed on CD34⁺CD38^- cells from FA patients with AML. We have examined whether the LIC 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 three FA AML samples, only IL-3R alpha-positive cells showed significant levels of engraftment and developed leukemia in the recipient mice. The FA CD34⁺IL-3R alpha⁺ blasts isolated from leukemic mice exhibited hypersensitivity to IL-3 deprivation and JAK2-STAT5 overactivation following IL-3 treatment. Finally, pretreatment of FA CD34⁺IL-3R alpha⁺ blasts with the IL-3Ra neutrolizing antibody inhibits IL-3-mediated proliferation and STAT5 activation. These results demonstrate that IL-3Ra is a cell surface marker present on FA AML-LIC and may serve a valuable therapeutic target.