期刊
CELL STEM CELL
卷 5, 期 1, 页码 31-42出版社
CELL PRESS
DOI: 10.1016/j.stem.2009.04.018
关键词
-
资金
- Children's Cancer Institute Australia for Medical Research
- CSL Limited
Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor a chain (CD123)-neutralizing antibody (7133) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7133 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with preestablished disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7133 inhibited IL-3-mediated intracellular signaling of isolated AML CD34(+) CD38(-) cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.
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