title: Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes.
abstract: Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count <10/mm(3) blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and deficiency of these cells was significantly associated with poor prognosis. In the second subgroup, comprising the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56(bright) cells. The residual CD56(dim) cells exhibited a significant increase of the unlicensed NKG2A(-)KIR(-) subset and a striking reduction in complexity of the repertoire of killer cell immunoglobulin-like receptors. Taken together, these results suggest that the widespread defects in natural killer cell function occurring in patients with myelodysplastic syndromes are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression through impaired immune surveillance.
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Maryam
authors: M
authors: Hejazi
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Angela R
authors: AR
authors: Manser
authors: Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Julia
authors: J
authors: Fröbel
authors: Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Andrea
authors: A
authors: Kündgen
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Xiaoyi
authors: X
authors: Zhao
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Kathrin
authors: K
authors: Schönberg
authors: Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Ulrich
authors: U
authors: Germing
authors: Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Rainer
authors: R
authors: Haas
authors: Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors: Norbert
authors: N
authors: Gattermann
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany Markus.Uhrberg@med.uni-duesseldorf.de.
authors: Markus
authors: M
authors: Uhrberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002454:Cell Differentiation; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality; D010641:Phenotype; D011379:Prognosis
chemical_list: D007376:Interleukin-2