1. Department of Pathology and New York University Cancer Institute,
2. Helen L. and Martin S. Kimmel Stem Cell Center,
3. Program in Molecular Pathogenesis, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA
4. Department of Pediatrics,
5. Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032, USA
6. Department of Gene and Cell Medicine, and the Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA
7. Division of Biostatistics, New York University Cancer Institute, New York, New York 10016, USA
8. Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany

Correspondence to: Iannis Aifantis^1,2 Correspondence and requests for materials should be addressed to I.A. (Email: iannis.aifantis@nyumc.org).

Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents¹. T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse^{2, 3}. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment³. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance⁴. Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine–receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.

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