TY - JOUR
T1 - Central nervous system acute lymphoblastic leukemia
T2 - Role of natural killer cells
AU - Frishman-Levy, Liron
AU - Shemesh, Avishai
AU - Bar-Sinai, Allan
AU - Ma, Chao
AU - Ni, Zhenya
AU - Frenkel, Shahar
AU - Muench, Vera
AU - Bruckmueller, Hilke
AU - Vokuhl, Christian
AU - Debatin, Klaus Michael
AU - Eckert, Cornelia
AU - Stanulla, Martin
AU - Schrappe, Martin
AU - Campbell, Kerry S.
AU - Loewenthal, Ron
AU - Schewe, Denis M.
AU - Hochman, Jacob
AU - Meyer, Lueder H.
AU - Kaufman, Dan
AU - Cario, Gunnar
AU - Porgador, Angel
AU - Izraeli, Shai
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/5/28
Y1 - 2015/5/28
N2 - 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 theNKG2Dand NKp44receptors.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.
AB - 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 theNKG2Dand NKp44receptors.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.
UR - http://www.scopus.com/inward/record.url?scp=84930941932&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-08-595108
DO - 10.1182/blood-2014-08-595108
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C2 - 25896649
AN - SCOPUS:84930941932
SN - 0006-4971
VL - 125
SP - 3420
EP - 3431
JO - Blood
JF - Blood
IS - 22
ER -
