title: 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 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.
authors.affiliation: Department of Pathology and New York University Cancer Institute, New York 10016, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Buonamici
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Ruocco
authors.forename: Linsey
authors.initials: L
authors.lastname: Reavie
authors.forename: Severine
authors.initials: S
authors.lastname: Cathelin
authors.forename: Brenton G
authors.initials: BG
authors.lastname: Mar
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Lukyanov
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Tseng
authors.forename: Filiz
authors.initials: F
authors.lastname: Sen
authors.forename: Eric
authors.initials: E
authors.lastname: Gehrie
authors.forename: Mengling
authors.initials: M
authors.lastname: Li
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Newcomb
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Daniel
authors.initials: D
authors.lastname: Meruelo
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.forename: Sherif
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Argiris
authors.initials: A
authors.lastname: Efstratiadis
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology*; D054415:Chemokine CCL19 / Q000172:deficiency / Q000378:metabolism; D054421:Chemokine CCL21 / Q000378:metabolism; D006801:Humans; D015458:Leukemia, T-Cell / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515370:CCR7 protein, human; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D051881:Receptor, Notch1; D054400:Receptors, CCR7