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Utilizing knockouts of potential AML ligands and CTL receptors, we demonstrate that pMHC-independent cytotoxicity is a potent mechanism of CTL-mediating killing of AML cells and is largely restricted to CD64-expressing cells through an IFN\u03b3-regulated process. Notably, we found that pMHC-independent CTL killing is not due to activation of commonly implicated NK activating receptors but rather requires an activated TCR\u03b1\u03b2\/CD3 complex. 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