Natural killer resistance of a drug-resistant leukemia cell line, mediated by up-regulation of HLA class I expression

Abstract

BACKGROUND AND OBJECTIVES: Drug-resistant leukemia cells may exhibit cross-resistance towards immunological effector mechanisms by alterations of apoptosis pathways. This is particularly relevant in allogeneic bone marrow transplantation for leukemia, where the graft-versus-leukemia effect acts on cells pretreated with cytostatic drugs. Here, we clarify the mechanism underlying cross-resistance of drug-resistant variants of the T-leukemia cell line CEM towards natural killer cells. DESIGN AND METHODS: We determined the sensitivity of different CEM sublines to natural killer (NK) cytotoxicity, and separately analyzed the components of the killing machinery by detection of granzyme B-induced caspase cleavage and HLA class I-dependent recognition mechanisms. Furthermore, we studied regulation of HLA class I expression comparing CEM with other cell lines. RESULTS: We found that CEM cells resistant to cytostatic drugs or CD95 were cross-resistant towards NK cells from a variety of donors. Granzyme B-induced caspase and PARP cleavage in the sensitive and resistant cells were comparable, indicating that downstream apoptosis pathways were not altered in the drug-resistant cells. HLA class I molecules were upregulated in the resistant cells, inhibiting NK cells at the level of killer/target recognition. HLA class I upregulation was not found in other leukemia cell lines. INTERPRETATION AND CONCLUSIONS: This is the first description of HLA class I-mediated NK cross-resistance in drug-resistant cells. This finding may have a clinical impact since it may be considered as a possible reason for resistance to a graft-versus-leukemia approach in allogeneic bone marrow transplantation