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Lymphotoxin-beta receptor and RANK signaling in TEL-JAK2-induced T-cell leukemia
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Advisor(s)
Abstract(s)
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.
Description
Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015
Keywords
Leucemia linfoblástica aguda de linfócitos T Modelo murino transgénico TEL-JAK2 Timo Microambiente tumoral Recetor da linfotoxina beta Fator nuclear κB