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

Lymphotoxin-mediated activation of the lymphotoxin-β receptor (LTβR; 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)-α and LTβ (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 LTα1 β2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTβR 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 LTβR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTβR signalling in thymic stromal cells, thus promoting leukaemogenesis.Grants from Fundação para a Ciencia e a Tecnologia (PTDC/SAU-OBD/103336/2008 and PEst-OE/EQB/LA0023/2013), Nucleo Regional Sul da Liga Portuguesa Contra o Cancro (NRS/LPCC-Terry Fox) and Fundacao MSD to NRdS; grants from the Sao Paulo Research Foundation (FAPESP 08/10034-1 and 12/12802-1) to JAY; and Plan Cancer Action 29 to ED. MTF (SFRH/BD/75137/2010) MNG (SFRH/BD/80503/2011), and RKK (SFRH/BPD/70718/2010) were recipients of FCT PhD or postdoctoral fellowships. ABS and JAY are supported by PhD and Productivity Fellowships, respectively, from the Brazilian National Council for Scientific and Technological Development (CNPq). NRdS has been supported by FCT Ciencia 2007 and FCT Investigator contracts (IF/00056/2012)