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

Author(s):Show less -

Fernandes, Monica T. ^{[1, 2]} ; Ghezzo, Marinella N. ^{[1, 2]} ; Silveira, Andre B. ^[3] ; Kalathur, Ravi K. ^[1] ; Povoa, Vanda ^[4] ; Ribeiro, Ana R. ^{[5, 6, 7]} ; Brandalise, Silvia R. ^[3] ; Dejardin, Emmanuel ^[8] ; Alves, Nuno L. ^{[5, 6]} ; Ghysdael, Jacques ^{[9, 10, 11]} ; Barata, Joao T. ^[4] ; Yunes, Jose Andres ^{[12, 3]} ; dos Santos, Nuno R. ^[1]

Affiliation:Show less -

^[1] Univ Algarve, Ctr Biomed Res CBMR, P-8005139 Faro - Portugal

^[2] Univ Algarve, Dept Biomed Sci & Med, P-8005139 Faro - Portugal

^[3] Ctr Infantil Boldrini, Campinas, SP - Brazil

^[4] Univ Lisbon, Fac Med, Inst Mol Med, P-1699 Lisbon - Portugal

^[5] Univ Porto, Inst Invest & Inovacao Saude, P-4100 Oporto - Portugal

^[6] Univ Porto, Inst Biol Mol & Celular, Thymus Dev & Funct Lab, P-4100 Oporto - Portugal

^[7] Univ Porto, Inst Biomed Sci Abel Salazar, P-4100 Oporto - Portugal

^[8] Univ Liege, GIGA Res, Lab Mol Immunol & Signal Transduct, Liege - Belgium

^[9] Ctr Univ, Inst Curie, Ctr Rech, Orsay - France

^[10] CNRS, UMR3306, Ctr Univ, F-91405 Orsay - France

^[11] INSERM U1005, Ctr Univ, Orsay - France

^[12] Univ Estadual Campinas, UNICAMP, Campinas, SP - Brazil

• Document type: Journal article
• Source: British Journal of Haematology; v. 171, n. 5, p. 736-751, DEC 2015.
• Web of Science Citations: 10

Abstract

Lymphotoxin-mediated activation of the lymphotoxin-beta receptor (LT beta R; 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 LIP (LTA, LTB) arc 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 TALL. Surface LT 132 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LT beta R 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 thymocytcs than age-matched TEL-JAK2;Ltbr(+/+) mice and interference with LT beta R function at this early stage delayed I-ALL development. We conclude that LT expression by T-ALL cells activates LT beta R signalling in thymic stromal cells, thus promoting leukaemogenesis. (AU)

• FAPESP's process: 12/12802-1 - Cooperating mutations, functional studies and antibodies against the mutant IL7R in acute lymphoblastic leukemia
• Grantee: José Andrés Yunes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 08/10034-1 - Bone marrow microenvironment and PI3K pathway in resistance to chemotherapy of pediatric acute lymphoblastic leukemia
• Grantee: José Andrés Yunes
• Support Opportunities: Regular Research Grants