title: Both mature KIR+ and immature KIR- NK cells control pediatric acute B-cell precursor leukemia in NOD.Cg-Prkdcscid IL2rgtmWjl/Sz mice.
abstract: Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B-cell precursor leukemia (BCP-ALL) appears to be resistant to NK-cell-mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. In this study, we demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity toward pediatric BCP-ALL in vivo. Notably, both adoptively transferred mature KIR(+) NK cells and immature KIR(-) NK cells arising early posttransplantation in humanized NSG mice exerted substantial antileukemic activity. Low-dose and long-term treatment of humanized NSG mice with the DNA-demethylating agent 5-aza-cytidine distinctly enhanced the antitumor response, interestingly without inducing common inhibitory KIR expression but rather by promoting the differentiation of various NK-cell precursor subsets. Collectively, these data indicate that the future design of innovative therapy protocols should consider further exploitation of NK-cell-mediated immune responses for poor prognosis pediatric BCP-ALL patients.
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Ayline
authors.initials: A
authors.lastname: Kübler
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Jeanette
authors.initials: J
authors.lastname: Woiterski
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Kai-Erik
authors.initials: KE
authors.lastname: Witte
authors.affiliation: Department of Internal Medicine II, Division of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Bühring
authors.affiliation: University Medical Center, 3 Department of Medicine/Hematology, Internal Oncology and Pneumology, Johannes Gutenberg-University, Mainz, Germany;
authors.forename: Udo F
authors.initials: UF
authors.lastname: Hartwig
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany; University Children's Hospital, Department for Pediatric Hematology and Oncology, Campus Virchow Klinikum, Charité Berlin, Berlin, Germany;
authors.forename: Lena
authors.initials: L
authors.lastname: Oevermann
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Mezger
authors.affiliation: University Medical Center, 3 Department of Medicine/Hematology, Internal Oncology and Pneumology, Johannes Gutenberg-University, Mainz, Germany; University of Regensburg, Department of Internal Medicine III, Regensburg, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Switzerland; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany; University Children's Hospital, Department of Pediatric Intensive Care, Basel, Switzerland.
authors.forename: Maya C
authors.initials: MC
authors.lastname: André
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001374:Azacitidine / Q000737:chemistry; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D019175:DNA Methylation; D004195:Disease Models, Animal; D005838:Genotype; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology*; D051379:Mice; D016688:Mice, Inbred NOD; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000628:therapy*; D011379:Prognosis; D054340:Receptors, KIR / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D007376:Interleukin-2; D054340:Receptors, KIR; D001374:Azacitidine