Back to Search
Start Over
Natural killer resistance of a drug-resistant leukemia cell line, mediated by up-regulation of HLA class I expression.
- Source :
-
Haematologica [Haematologica] 2003 May; Vol. 88 (5), pp. 509-21. - Publication Year :
- 2003
-
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.<br />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.<br />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.<br />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
- Subjects :
- Antineoplastic Agents pharmacology
Caspases metabolism
Cell Nucleus ultrastructure
Cells, Cultured
Cytotoxicity, Immunologic
DNA Fragmentation
Doxorubicin pharmacology
Granzymes
Humans
Leukemia, T-Cell drug therapy
Lysosomes physiology
Poly(ADP-ribose) Polymerases metabolism
Serine Endopeptidases metabolism
Tumor Cells, Cultured
Up-Regulation
fas Receptor immunology
Drug Resistance, Neoplasm
HLA Antigens biosynthesis
Histocompatibility Antigens Class I biosynthesis
Killer Cells, Natural immunology
Leukemia, T-Cell immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 88
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 12745270