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

作者：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^*

来源：Blood, 2015, 125(22): 3420-3431.

DOI：10.1182/blood-2014-08-595108

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.

• 出版日期2015-5-28