Publication
Lymphotoxin-beta receptor and RANK signaling in TEL-JAK2-induced T-cell leukemia
| datacite.subject.fos | Ciências Médicas::Biotecnologia Médica | pt_PT |
| dc.contributor.advisor | Santos, Nuno Rodrigues dos | |
| dc.contributor.author | Fernandes, Mónica Alexandra Teotónio | |
| dc.date.accessioned | 2016-12-15T11:33:43Z | |
| dc.date.available | 2016-12-15T11:33:43Z | |
| dc.date.issued | 2015-09-16 | |
| dc.date.submitted | 2015 | |
| dc.description | Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015 | |
| dc.description.abstract | T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy that arises from the combination of genetic and epigenetic alterations in thymic T-cell precursors and extracellular signals provided by the microenvironment. It was previously found that RelB expression in non-hematopoietic stromal cells promoted T-cell leukemogenesis in the EμSRalpha-TEL-JAK2 transgenic (TJ2-Tg) mouse model. In thymic stromal cells, RelB is a transcription mediator of lymphotoxin-beta receptor (LTβR). Lymphotoxin-mediated activation of LTβR has been implicated in physiological crosstalk between T cells and lymphoid organ stromal cells, but also pathological processes, including carcinogenesis. Since its role in T-ALL has remained elusive, we aimed to determine whether LTβR signaling is activated and playing a role in TEL-JAK2-induced leukemogenesis. In TJ2-Tg thymic lymphomas, activation of LTα1β2-LTβR signaling axis was supported by LTβRencoding gene expression, while the genes encoding its cognate ligand, lymphotoxin (LT)-α and LTβ, were found to be expressed by leukemic T cells, in an NF-κB-dependent manner. LTα1β2 protein was detected at the surface of TJ2-Tg leukemic cells only upon ex vivo culture or mitogenic stimulation. Moreover, we found that cell-surface LTα1β2 is downmodulated in vivo, indicating ongoing signaling. Further supporting a role for lymphotoxin signaling, LTβR genetic deficiency delayed TEL-JAK2-induced leukemia onset, but the tumor load in lymphoid organs and leukemia cell surface phenotype were comparable in end-stage disease. In accordance, the detection of reduced proportions of malignant thymocytes in TJ2-Tg;Ltbr-/- mice with no signs of disease implicated LTβR in early stages of leukemia development. Together, these data indicate that T-ALL-derived lymphotoxin activates LTβR signaling in thymic stromal cells, promoting leukemogenesis. Importantly, lymphotoxin-encoding genes were expressed in T-ALL patient samples, indicating that these may be also involved in human disease. Thus, future studies should provide a better understanding on how cellular crosstalk mediated by the lymphotoxin-LTβR axis supports T-ALL and assess the utility of blocking LTβR signaling as a novel therapeutic approach. | pt_PT |
| dc.identifier.tid | 101317085 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10400.1/8849 | |
| dc.language.iso | eng | pt_PT |
| dc.relation | LYMPHOTOXIN-BETA RECEPTOR AND RANK SIGNALING IN TEL-JAK2-INDUCED T-CELL LEUKEMIA | |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt_PT |
| dc.subject | Leucemia linfoblástica aguda de linfócitos T | pt_PT |
| dc.subject | Modelo murino transgénico TEL-JAK2 | pt_PT |
| dc.subject | Timo | pt_PT |
| dc.subject | Microambiente tumoral | pt_PT |
| dc.subject | Recetor da linfotoxina beta | pt_PT |
| dc.subject | Fator nuclear κB | pt_PT |
| dc.title | Lymphotoxin-beta receptor and RANK signaling in TEL-JAK2-induced T-cell leukemia | pt_PT |
| dc.type | doctoral thesis | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | LYMPHOTOXIN-BETA RECEPTOR AND RANK SIGNALING IN TEL-JAK2-INDUCED T-CELL LEUKEMIA | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F75137%2F2010/PT | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | doctoralThesis | pt_PT |
| relation.isProjectOfPublication | 266dce2a-742e-40ee-ba73-31f1e7aec83a | |
| relation.isProjectOfPublication.latestForDiscovery | 266dce2a-742e-40ee-ba73-31f1e7aec83a | |
| thesis.degree.grantor | Departamento de Ciências Biomédicas e Medicina | |
| thesis.degree.level | Doutor | |
| thesis.degree.name | Doutoramento em Ciências Biomédicas | pt_PT |