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

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