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Type: Journal article
Title: Monoclonal antibody-mediated targeting of CD123, IL-3 receptor α chain, eliminates human acute myeloid leukemic stem cells
Other Titles: Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells
Author: Jin, L.
Lee, E.
Ramshaw, H.
Busfield, S.
Peoppl, A.
Wilkinson, L.
Guthridge, M.
Thomas, D.
Barry, E.
Boyd, A.
Gearing, D.
Vairo, G.
Lopez, A.
Dick, J.
Lock, R.
Citation: Cell Stem Cell, 2009; 5(1):31-42
Publisher: Cell Press
Issue Date: 2009
ISSN: 1934-5909
Statement of
Liqing Jin, Erwin M. Lee, Hayley S. Ramshaw, Samantha J. Busfield, Armando G. Peoppl, Lucy Wilkinson, Mark A. Guthridge, Daniel Thomas, Emma F. Barry, Andrew Boyd, David P. Gearing, Gino Vairo, Angel F. Lopez, John E. Dick, and Richard B. Lock
Abstract: 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 alpha chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 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.
Keywords: Stemcell
Rights: Copyright © 2009 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.stem.2009.04.018
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