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Stemming the tide of leukemia development
Acute myeloid leukemia and myelodysplastic syndromes are maintained by specific populations of malignant stem cells, and successful treatment requires the eradication of these disease-causing cells. Chung et al. identified CD99 as a marker expressed on the surface of leukemic stem cells but not normal hematopoietic stem cells, suggesting its potential as a therapeutic target. A monoclonal antibody against CD99 had promising preclinical effectiveness in xenograft models and was selective for malignant stem cells, paving the way for further development of this approach.
Abstract
Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) are initiated and sustained by self-renewing malignant stem cells; thus, eradication of AML and MDS stem cells is required for cure. We identified CD99 as a cell surface protein frequently overexpressed on AML and MDS stem cells. Expression of CD99 allows for prospective separation of leukemic stem cells (LSCs) from functionally normal hematopoietic stem cells in AML, and high CD99 expression on AML blasts enriches for functional LSCs as demonstrated by limiting dilution xenotransplant studies. Monoclonal antibodies (mAbs) targeting CD99 induce the death of AML and MDS cells in a SARC family kinase–dependent manner in the absence of immune effector cells or complement, and anti-CD99 mAbs exhibit antileukemic activity in AML xenografts. These data establish CD99 as a marker of AML and MDS stem cells, as well as a promising therapeutic target in these disorders.
- Copyright © 2017, American Association for the Advancement of Science
