Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype
| العنوان: | Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype |
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| المؤلفون: | João T. Barata, Vanda Póvoa, Nuno R. dos Santos, Emmanuel Dejardin, Jacques Ghysdael, José Andrés Yunes, Ana R. Ribeiro, Silvia Regina Brandalise, Nuno L. Alves, André B. Silveira, Ravi Kiran Reddy Kalathur, Mónica T. Fernandes, Marinella N. Ghezzo |
| المساهمون: | Instituto de Investigação e Inovação em Saúde, Repositório da Universidade de Lisboa |
| المصدر: | British Journal of Haematology Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | T-cell acute lymphoblastic leukaemia, Lymphotoxin-beta receptor, Carcinogenesis, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics, Tumor Microenvironment/genetics, Molecular Sequence Data, Gene Expression, Mice, Transgenic, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Lymphotoxin beta Receptor/metabolism, Immunophenotyping, Cell Lineage/genetics, Lymphotoxin beta Receptor, hemic and lymphatic diseases, Cell Line, Tumor, Tumor Microenvironment, Animals, Humans, Cell Lineage, Tumour-stromal interactions, Mice, Knockout, Tumour microenvironment, Janus Kinase 2/genetics, Lymphotoxin, Hematology, Janus Kinase 2, Lymphotoxin beta Receptor/genetics, Gene Expression/genetics, Lymphotoxin beta Receptor/physiology, Cancer research, Carcinogenesis/genetics, Lymphotoxin beta receptor, Signal Transduction |
| الوصف: | © 2015 John Wiley & Sons Ltd. 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 Ciência e a Tecnologia (PTDC/SAU-OBD/103336/2008 and PEst-OE/EQB/LA0023/2013), Núcleo Regional Sul da Liga Portuguesa Contra o Cancro (NRS/LPCC-Terry Fox) and Fundação MSD to NRdS; grants from the São 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 Ciência 2007 and FCT Investigator contracts (IF/00056/2012). |
| وصف الملف: | application/pdf |
| تدمد: | 0007-1048 |
| DOI: | 10.1111/bjh.13760 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b59ecfff260cd646765a2e369fddfb49Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b59ecfff260cd646765a2e369fddfb49 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00071048 |
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| DOI: | 10.1111/bjh.13760 |