- 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 since 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 diagnostic samples derived from children with subsequent CNS-ALL revealed a significant high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunological sanctuary protected from NK cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell based therapies against hematopoietic malignancies. Copyright © 2015 American Society of Hematology.