TY - JOUR
T1 - CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia
AU - Buonamici, Silvia
AU - Trimarchi, Thomas
AU - Ruocco, Maria Grazia
AU - Reavie, Linsey
AU - Cathelin, Severine
AU - Mar, Brenton G.
AU - Klinakis, Apostolos
AU - Lukyanov, Yevgeniy
AU - Tseng, Jen Chieh
AU - Sen, Filiz
AU - Gehrie, Eric
AU - Li, Mengling
AU - Newcomb, Elizabeth
AU - Zavadil, Jiri
AU - Meruelo, Daniel
AU - Lipp, Martin
AU - Ibrahim, Sherif
AU - Efstratiadis, Argiris
AU - Zagzag, David
AU - Bromberg, Jonathan S.
AU - Dustin, Michael L.
AU - Aifantis, Iannis
N1 - Funding Information:
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.
PY - 2009/6/18
Y1 - 2009/6/18
N2 - T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. 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. 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 impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. 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.
AB - T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. 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. 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 impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. 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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U2 - 10.1038/nature08020
DO - 10.1038/nature08020
M3 - Article
C2 - 19536265
AN - SCOPUS:67649249962
SN - 0028-0836
VL - 459
SP - 1000
EP - 1004
JO - Nature
JF - Nature
IS - 7249
ER -