Children and adolescents diagnosed with T cell acute lymphoblastic leukaemia (T-ALL) are often treated with cranial radiotherapy and chemotherapy injected into the cerebrospinal fluid to reduce the risk of central nervous system (CNS) relapse. Although this increases long-term survival, the side effects can be considerable. Iannis Aifantis and colleagues have identified a chemokine receptor, CCR7, as being crucial for CNS infiltration, paving the way for reducing the toxicity of treatments used to prevent CNS relapse.

...the CCR7 receptor–ligand pathway is necessary and sufficient for CNS infiltration of T-ALL cells...

Given that activation of the NOTCH1 pathway occurs in more than 80% of patients with T-ALL, the authors investigated whether thederegulation of this pathway influences CNS infiltration. They reasoned that T-ALL cells able to enter the CNS would need to adhere to their new microenvironment, so they looked for adhesion regulators with increased expression in haematopoietic progenitors expressing the active intracellular fragment of NOTCH1 (NOTCH1-IC). Genome- wide expression studies indicated that Ccr7 was a potential candidate. T-ALL cell lines with activated NOTCH1 and peripheral blood samples from patients with T-ALL showed that CCR7 expression was strongly associated with NOTCH1 activation. Suppression of NOTCH1 activity using a γ-secretase inhibitor that prevents cleavage and activation of NOTCH1 reduced the expression levels of CCR7 mRNA.

In vivo, the authors found that syngeneic mice transplanted with Ccr7-wild-type or -null haematopoietic progenitors expressing NOTCH1-IC had different rates of disease progression. Mice with Ccr7-null cells had a prolonged survival rate compared with their Ccr7-expressing counterparts and although T-ALL cells were evident in lymphoid organs in both mouse models, CNS infiltration was significantly reduced in mice with Ccr7-null leukaemic cells. Interestingly, deletion of Ccr7 in two mouse models of B cell ALL failed to inhibit CNS infiltration, indicating that CCR7 has a specific function in T-ALL cells with activated NOTCH1.

CCR7 is bound by CCL21 and CCL19, so are both ligands important for CNS infiltration? Immunohistochemical analyses indicated that only CCL19 was expressed in brain tissue samples taken from mice with T-ALL. Moreover, CNS infiltration in plt mice, which naturally lack expression of both CCL21 and CCL19, was significantly reduced compared with wild-type mice. Therefore, the CCR7 receptor–ligand pathway is necessary and sufficient for CNS infiltration of T-ALL cells; however, other adhesionmolecules are also likely to be important.