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Permanent cure of acute myeloid leukemia (AML) by chemotherapy alone remains elusive for most patients because of the inability to effectively eradicate leukemic stem cells (LSCs), the self-renewing component of the leukemia. To develop therapies that effectively target LSC, one potential strategy is to identify cell surface markers that can distinguish LSC from normal hematopoietic stem cells (HSCs). In this study, we employ a signal sequence trap strategy to isolate cell surface molecules expressed on human AML-LSC and find that CD96, which is a member of the Ig gene superfamily, is a promising candidate as an LSC-specific antigen. FACS analysis demonstrates that CD96 is expressed on the majority of CD[34.sup.+]CD[38.sup.-] AML cells in many cases (74.0 [+ or -] 25.3% in 19 of 29 cases), whereas only a few (4.9 [+ or -] 1.6%) cells in the normal HSC-enriched population ([Lin.sup.-]CD[34.sup.+]CD[38.sup.-]CD[90.sup.+]) expressed CD96 weakly. To examine whether CD[96.sup.+] AML cells are enriched for LSC activity, we separated AML cells into CD[96.sup.+] and CD[96.sup.-] fractions and transplanted them into irradiated newborn Rag[2.sup.-/-] [gamma][c.sup.-/-] mice. In four of five samples, only CD[96.sup.+] cells showed significant levels of engraftment in bone marrow of the recipient mice. These results demonstrate that CD96 is a cell surface marker present on many AML-LSC and may serve as an LSC-specific therapeutic target. hematopoietic stem cell