Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells
Autor: | Lucy Wilkinson, Andrew W. Boyd, Gino Vairo, Armando G. Peoppl, Erwin M. Lee, Samantha J. Busfield, Hayley S. Ramshaw, David Gearing, Angel F. Lopez, Daniel Thomas, Liqing Jin, Richard B. Lock, John E. Dick, Mark A. Guthridge, Emma F Barry |
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Přispěvatelé: | Jin, Liqing, Lee, Erwin M, Ramshaw, Hayley S, Busfield, Samantha J, Peoppl, Armando G, Wilkinson, Lucy, Guthridge, Mark A, Thomas, Daniel, Barry, Emma F, Boyd, Andrew, Gearing, David P, Vairo, Gino, Lopez, Angel, Dick, John E, Lock, Richard B |
Jazyk: | angličtina |
Předmět: |
Adult
Male Myeloid Transplantation Heterologous Interleukin-3 Receptor alpha Subunit monoclonal Antigens CD34 Mice SCID Biology Cell Line Mice Bone Marrow Cell Movement Mice Inbred NOD hemic and lymphatic diseases Genetics medicine Animals Humans Interleukin 3 Aged Cell Proliferation Aged 80 and over myeloid leukemic stem cells Intracellular Signaling Peptides and Proteins Myeloid leukemia Antibodies Monoclonal Cell Biology antibody-mediated targeting Middle Aged medicine.disease Colony-stimulating factor Hematopoietic Stem Cells STEMCELL Tumor Burden Transplantation Leukemia Leukemia Myeloid Acute medicine.anatomical_structure CD123 Immunology Neoplastic Stem Cells Molecular Medicine Female IL-3 receptor a chain Bone marrow Stem cell Stem Cell Transplantation |
Zdroj: | Cell Stem Cell. (1):31-42 |
ISSN: | 1934-5909 |
DOI: | 10.1016/j.stem.2009.04.018 |
Popis: | 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 α 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. Refereed/Peer-reviewed |
Databáze: | OpenAIRE |
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