Lymphotoxin-β receptor expression in microenvironmental cells promotes the development of leukemia

Authors and Affiliations:
Mónica T. Fernandes^1,2, Marinella N. Ghezzo^1,2, André B. Silveira^3, Ravi K. Kalathur¹, Vanda Póvoa^4, Ana R. Ribeiro^5,6,7, Sílvia R. Brandalise³, Emmanuel Dejardin⁸, Nuno L. Alves^5,6, Jacques Ghysdael ^9,10,11, João T. Barata^4, José Andres Yunes^3,12, and Nuno R. dos Santos¹

₁ Centre for Biomedical Research (CBMR), University of Algarve, 8005-139 Faro, Portugal;

² PhD Program in Biomedical Sciences, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal;

³ Centro Infantil Boldrini, Campinas, São Paulo, Brazil;

⁴ Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal;

⁵ Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal

⁶ Instituto de Biologia Molecular e Celular, Thymus Development and Function Laboratory, Universidade do Porto, Porto, Portugal;

⁷ Doctoral Program in Biomedical Sciences, Institute for Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal;

⁸ Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, 4000 Liège, Belgium;

⁹ Institut Curie-Centre de Recherche, Centre Universitaire, 91405 Orsay, France;

¹⁰ CNRS UMR3306, Centre Universitaire, 91405 Orsay, France;

¹¹ INSERM U1005, Centre Universitaire, 91405 Orsay, France;

¹² Department of Pediatrics, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Abstract:
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 LTα1β2 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.

Journal: British Journal of Haematology

Link: http://onlinelibrary.wiley.com/doi/10.1111/bjh.13760/abstract