Cytarabine-resistant AML cell lines or blasts from refractory AML express some of the ligands for the NK-activating receptor NKG2D. This expression is associated with c-Myc induction. Hence, at least ULBP1 and ULBP3 have c-Myc docking sites in their gene promoter. The upregulation of ULBPs by leukemic cells renders the cells more susceptible to in vitro NK-cell–mediated lysis. The study by Nanbakhsh et al raises several questions. Usually, cytarabine is not used as a single reagent but in combination with anthracyclines; this combination has not been tested by the authors. As chemotherapy drugs usually trigger the DDR pathway, it would be interesting to replace the ATM/ATR pathway in that context. Furthermore, AML-NK recognition has also been attributed to NCRs and DNAM-1. It would then be interesting to study the expression of the ligands for these receptors by AML cells after chemotherapy treatment. HLA-I expression by leukemic cells is also an escape mechanism. Is c-Myc or simply cytarabine associated with HLA upregulation or downregulation? Finally, phenotypically and functionally defective NK cells have often been described in AML. Consequently, the expression of NKG2DL might not result in an increased sensitivity to NK-cell killing in patients. These questions summarize the up-to-date challenges in drug-resistant AML treatment. ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; DNAM-1-L, DNAX accessory molecule-1-ligands; NCR-L, natural cytotoxicity receptors-ligands. Professional illustration by Xavier Studio.