Lymphotoxin-beta receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype.

Lymphotoxin-mediated activation of the lymphotoxin-beta receptor (LTbetaR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-alpha and LTbeta (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTalpha1 beta2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTbetaR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr-/- mice present markedly less leukaemic thymocytes than age-matched TEL-JAK2;Ltbr+/+ mice and interference with LTbetaR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTbetaR signalling in thymic stromal cells, thus promoting leukaemogenesis.