title: Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype.
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 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.
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.|Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
authors.forename: Mónica T
authors.initials: MT
authors.lastname: Fernandes
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.|Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
authors.forename: Marinella N
authors.initials: MN
authors.lastname: Ghezzo
authors.affiliation: Centro Infantil Boldrini, Campinas, SP, Brazil.
authors.forename: André B
authors.initials: AB
authors.lastname: Silveira
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Kalathur
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Vanda
authors.initials: V
authors.lastname: Póvoa
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Thymus Development and Function Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.|Institute for Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Ribeiro
authors.affiliation: Centro Infantil Boldrini, Campinas, SP, Brazil.
authors.forename: Sílvia R
authors.initials: SR
authors.lastname: Brandalise
authors.affiliation: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dejardin
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Thymus Development and Function Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Nuno L
authors.initials: NL
authors.lastname: Alves
authors.affiliation: Institut Curie-Centre de Recherche, Centre Universitaire, Orsay, France.|CNRS UMR3306, Centre Universitaire, Orsay, France.|INSERM U1005, Centre Universitaire, Orsay, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Ghysdael
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: João T
authors.initials: JT
authors.lastname: Barata
authors.affiliation: Centro Infantil Boldrini, Campinas, SP, Brazil.|Department of Paediatrics, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: José Andres
authors.initials: JA
authors.lastname: Yunes
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
authors.forename: Nuno R
authors.initials: NR
authors.lastname: dos Santos
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D053614:Janus Kinase 2 / Q000235:genetics; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2
keywords: T-cell acute lymphoblastic leukaemia; lymphotoxin; lymphotoxin-beta receptor; tumour microenvironment; tumour-stromal interactions