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

Liron Frishman-Levy, Avishai Shemesh, Allan Bar-Sinai, Chao Ma, Zhenya Ni, Shahar Frenkel, Vera Muench, Hilke Bruckmueller, Christian Vokuhl, Klaus Michael Debatin, Cornelia Eckert, Martin Stanulla, Martin Schrappe, Kerry S. Campbell, Ron Loewenthal, Denis M. Schewe, Jacob Hochman, Lueder H. Meyer, Dan Kaufman, Gunnar CarioAngel Porgador, Shai Izraeli

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3420-3431
Number of pages12
JournalBlood
Volume125
Issue number22
DOIs
StatePublished - May 28 2015

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