Overexpression of IL-3Rα on CD34+CD38− stem cells defines leukemia-initiating cells in Fanconi anemia AML
| Autor: | Jared Sipple, Xue Li, Qishen Pang, Wei Du |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Hematopoiesis and Stem Cells
Transplantation Heterologous Immunology Interleukin-3 Receptor alpha Subunit CD34 Antigens CD34 CD38 Biology Biochemistry Mice Antigen Mice Inbred NOD Fanconi anemia hemic and lymphatic diseases STAT5 Transcription Factor medicine Animals Humans Interleukin 3 Stem Cells Myeloid leukemia Cell Biology Hematology Janus Kinase 2 medicine.disease ADP-ribosyl Cyclase 1 Up-Regulation Leukemia Myeloid Acute Leukemia Fanconi Anemia Cancer research Stem cell |
| Zdroj: | Blood. 117:4243-4252 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2010-09-309179 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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