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Frishman-Levy L , Shemesh A , Bar-Sinai A , Ma C , Ni Z , Frenkel S , Muench V , Bruckmueller H , Vokuhl C , Debatin KM , Eckert C , Stanulla M , Schrappe M , Campbell KS , Loewenthal R , Schewe DM , Hochman J , Meyer LH , Kaufman D , Cario G , Porgador A , Izraeli S
Central nervous system acute lymphoblastic leukemia: role of natural killer cells
Blood. 2015 May 28;125(22) :3420-31
PMID: 25896649    PMCID: PMC7265786    URL: http://www.ncbi.nlm.nih.gov/pubmed/25896649
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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.
Frishman-Levy, Liron Shemesh, Avishai Bar-Sinai, Allan Ma, Chao Ni, Zhenya Frenkel, Shahar Muench, Vera Bruckmueller, Hilke Vokuhl, Christian Debatin, Klaus Michael Eckert, Cornelia Stanulla, Martin Schrappe, Martin Campbell, Kerry S Loewenthal, Ron Schewe, Denis M Hochman, Jacob Meyer, Lueder H Kaufman, Dan Cario, Gunnar Porgador, Angel Izraeli, Shai Blood. 2015 Apr 20. pii: blood-2014-08-595108.