title: Central nervous system acute lymphoblastic leukemia: role of natural killer cells.
abstract: Central nervous system acute lymphoblastic leukemia (CNS-ALL) is a major clinical problem. Prophylactic therapy is neurotoxic, and a third of the relapses involve the CNS. Increased expression of interleukin 15 (IL-15) in leukemic blasts is associated with increased risk for CNS-ALL. Using in vivo models for CNS leukemia caused by mouse T-ALL and human xenografts of ALL cells, we demonstrate that expression of IL-15 in leukemic cells is associated with the activation of natural killer (NK) cells. This activation limits the outgrowth of leukemic cells in the periphery, but less in the CNS because NK cells are excluded from the CNS. Depletion of NK cells in NOD/SCID mice enabled combined systemic and CNS leukemia of human pre-B-ALL. The killing of human leukemia lymphoblasts by NK cells depended on the expression of the NKG2D receptor. Analysis of bone marrow (BM) diagnostic samples derived from children with subsequent CNS-ALL revealed a significantly high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunologic sanctuary protected from NK-cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell-based therapies against hematopoietic malignancies.
authors.affiliation: Childhood Leukemia Research Section, Department of Pediatric Oncology and the Cancer Research Center, Edmond and Lily Safra Children Hospital and Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel;
authors.forename: Liron
authors.initials: L
authors.lastname: Frishman-Levy
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel;
authors.forename: Avishai
authors.initials: A
authors.lastname: Shemesh
authors.affiliation: Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel;
authors.forename: Allan
authors.initials: A
authors.lastname: Bar-Sinai
authors.affiliation: Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, MN;
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, MN;
authors.forename: Zhenya
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Ocular Oncology Service, Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
authors.forename: Shahar
authors.initials: S
authors.lastname: Frenkel
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany;
authors.forename: Vera
authors.initials: V
authors.lastname: Muench
authors.affiliation: Department of Pediatrics, University Hospital Schleswig Holstein, Kiel, Germany;
authors.forename: Hilke
authors.initials: H
authors.lastname: Bruckmueller
authors.affiliation: Department of Pediatric Pathology, University Hospital Schleswig Hostein, Kiel, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Vokuhl
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany;
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité Universitäts Medizin Berlin, Berlin, Germany;
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Department of Pediatric Oncology, Hannover Medical School, Hannover, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Department of Pediatrics, University Hospital Schleswig Holstein, Kiel, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: The Research Institute of Fox Chase Cancer Center, Philadelphia, PA; and.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.affiliation: Tissue Typing Laboratory and National Laboratory for Solid Organ Transplants, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Loewenthal
authors.affiliation: Department of Pediatrics, University Hospital Schleswig Holstein, Kiel, Germany;
authors.forename: Denis M
authors.initials: DM
authors.lastname: Schewe
authors.affiliation: Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel;
authors.forename: Jacob
authors.initials: J
authors.lastname: Hochman
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany;
authors.forename: Lueder H
authors.initials: LH
authors.lastname: Meyer
authors.affiliation: Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, MN;
authors.forename: Dan
authors.initials: D
authors.lastname: Kaufman
authors.affiliation: Department of Pediatrics, University Hospital Schleswig Holstein, Kiel, Germany;
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel;
authors.forename: Angel
authors.initials: A
authors.lastname: Porgador
authors.affiliation: Childhood Leukemia Research Section, Department of Pediatric Oncology and the Cancer Research Center, Edmond and Lily Safra Children Hospital and Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel;
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D016543:Central Nervous System Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology
chemical_list: D019409:Interleukin-15