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CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia

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) relapse2,3. 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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Figure 1: Notch1 activation induces T-ALL and targets leukaemic cells into the CNS.
Figure 2: CCR7 expression and response to CCL19/CCL21 is induced by Notch1 activation.
Figure 3: CCR7 expression is sufficient for CNS infiltration of human T-ALL cells.
Figure 4: CCR7–CCL19 interactions are essential for CNS infiltration in an animal model of T-ALL.

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Acknowledgements

We are grateful to G. Randolph, E. Kuan and T. Vilimas for technical help and discussions. We would like to thank P. Lopez and G. De La Cruz for cell sorting; D. Littman, W. Carroll, E. Raetz, S. Lira and S. Schwab for advice and illuminating discussions; C. Loomis and the Histology Facility for advice and troubleshooting tips. This work was supported by the National Institutes of Health (RO1CA105129, RO1CA133379, R56AI070310, P30CA016087 to I.A., RO1AI41428, RO1AI072039 to J.S.B.), the American Cancer Society (RSG0806801 to I.A.), the Dana Foundation, The Chemotherapy Foundation, the Alex’s Lemonade Stand Foundation (to I.A.), the Lauri Strauss Leukemia Foundation (to F.S.), the G&P Foundation, NYU Molecular Oncology and Immunology training grant (to S.B.), American Society of Hematology (to S.B.), Juvenile Diabetes Research Foundation (JDRFI1-2008-90 and 5-2008-236 to J.S.B.), the National Cancer Institute (1 P01 CA97403, Project 2 to A.E.) and a gift from the Berrie Foundation (to A.E.). A.K. was supported by a Fellowship from the Jane Coffin Childs Memorial Fund for Medical Research.

Author Contributions S.B., B.G.M. and I.A. designed experiments, performed experiments and wrote the manuscript. M.L.D., M.Li and M.G.R. performed the in vivo two-photon microscopy experiments and analysis. D.M. and J.-C.T. performed the bioluminescent imaging experiments. A.K. and A.E. generated the EF1-Notch1-IC mice. J.Z. performed the microarray data mining. Y.L., E.N. and D.Z. performed in the CNS pathology analysis. M.Lipp and J.S.B. assisted with experimental design, provided reagents and advice. T.T., L.R., S.C. and E.G. performed experiments.

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Correspondence to Iannis Aifantis.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12 with Legends and Supplementary Table 1. (PDF 9868 kb)

Supplementary Movie 1

This movie is a time-lapse movie acquired by using a 2-photon microscope of WTNI-IC cells in the lymph nodes. Leukemic cells are in green (EGFP), blood vessels are in red (Quantum Dots), in blue is the capsule of the lymph node (second harmonic). (MOV 2319 kb)

Supplementary Movie 2

This file is a time-lapse movie acquired by using a 2-photon microscope of CCR7-KON1-IC cells in the lymph nodes. Leukemic cells are in green (EGFP), blood vessels are in red (Quantum Dots), in blue is the capsule of the lymph node (second harmonic). (MOV 3150 kb)

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Buonamici, S., Trimarchi, T., Ruocco, M. et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459, 1000–1004 (2009). https://doi.org/10.1038/nature08020

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