Publicação

Unraveling the role of lymphotoxin signaling in T-cell acute leukemia molecular crosstalk with microenvironmental cells

Detalhes bibliográficos
Resumo:	The tumor microenvironment influences the initiation and progression of hematological malignancies. However, relatively little is known about the identity and function of microenvironmental factors participating in T-cell acute lymphoblastic leukemia (T-ALL) development. T-ALL is an aggressive malignancy, fatal without early diagnosis and therapy, affecting mainly children and adolescents, and with poor prognosis upon relapse. In T-ALL patients, malignant cells may occur in distinct microenvironmental niches such as blood, bone marrow (BM), and lymphoid organs. Such niches and molecular factors there produced are likely important for maintenance and disease progression, but so far only a few microenvironmental factors have been shown to favor T-ALL progression in mice, such as interleukin 7 and certain chemokines. Transgenic mice expressing the TEL-JAK2 fusion protein develop T-ALL with short latency and full penetrance. It was found that TEL-JAK2 leukemic cells express lymphotoxin (LT) proteins from the early stages of the disease 1. Supporting the notion that lymphotoxin promotes leukemogenesis, it was found that genetic inactivation of the LTβ receptor (LTβR) in TEL-JAK2 mice impaired T-ALL development 1. These results suggested that LT mediates molecular crosstalk between malignant and stromal non-malignant cells, thus favoring leukemogenesis. Therefore, we aimed to understand how LTβR activation in stromal cells can facilitate T-cell leukemogenesis. To this end, we tested a hypothesis: lymphotoxin-expressing leukemic cells activate LTβR signaling in stromal cells. To test this hypothesis, we co-cultured LT-expressing leukemic cells with fibroblast (NIH3T3) or BM-derived stromal (MS-5) cell lines stably transduced with a lentiviral construct expressing a luciferase reporter gene under control of an NF-kB-responsive transcriptional promoter. We found that leukemic cells activated the NF-kB reporter in transduced MS-5 cells and NIH3T3 fibroblasts, and confirmed that these cell line express LTβR. Next, we observed that luciferase activity in co-cultures was blocked by LTβR-Fc, a soluble inhibitory protein, thus showing that NF-kB activation was indeed mediated through LTβR stimulation. In addition, NF-kB reporter induction by cocultured leukemic cells was impaired in LTβR gene-deficient mouse embryonic fibroblasts. In conclusion, LT-expressing leukemic cells can indeed activate LTβR signaling in neighboring stromal cells. Considering these results, we will in the future identify LTβR-dependent transcriptional programs induced in stromal cells by leukemic cells.
Autores principais:	Araújo, Marta Alexandra Senra
Assunto:	T-cell acute lymphoblastic leukemia Microenvironment NF- kB pathway LTα1β2/LTβR signaling pathway TEL-JAK2 mouse model Leucemia linfoblástica aguda de linfócitos T Microambiente Via NF-kB Via de sinalização LTα1β2/LTβR Modelo murganho transgénico TEL-JAK2
Ano:	2017
País:	Portugal
Tipo de documento:	dissertação de mestrado
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade do Minho
Idioma:	inglês
Origem:	RepositóriUM - Universidade do Minho