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Blood. 2015 May 28;125(22):3420-31. doi: 10.1182/blood-2014-08-595108. Epub 2015 Apr 20.

Central nervous system acute lymphoblastic leukemia: role of natural killer cells.

Author information

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;
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;
Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel;
Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, MN;
Ocular Oncology Service, Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany;
Department of Pediatrics, University Hospital Schleswig Holstein, Kiel, Germany;
Department of Pediatric Pathology, University Hospital Schleswig Hostein, Kiel, Germany;
Department of Pediatric Oncology/Hematology, Charité Universitäts Medizin Berlin, Berlin, Germany;
Department of Pediatric Oncology, Hannover Medical School, Hannover, Germany;
The Research Institute of Fox Chase Cancer Center, Philadelphia, PA; and.
Tissue Typing Laboratory and National Laboratory for Solid Organ Transplants, Sheba Medical Center, Ramat Gan, Israel.

Erratum in

  • Blood. 2015 Jul 16;126(3):425.


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.

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