LYMPHOTOXIN-BETA RECEPTOR AND RANK SIGNALING IN TEL-JAK2-INDUCED T-CELL LEUKEMIA

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Cdkn2a inactivation promotes malignant transformation of mouse immature thymocytes before the β-selection checkpoint

Publication . Catarino, Telmo A.; Pacheco-Leyva, Ivette; Kindi, Faiza Al; Ghezzo, Marinella N.; Fernandes, Mónica T.; Costa, Telma; Rodrigues Dos Santos, Nuno

CDKN2A deletion is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia (T-ALL), occurring across all molecular and immunophenotypic subtypes. CDKN2A encodes two functionally unrelated tumor suppressor proteins, ARF and INK4a, which are critical regulators of cell cycle and proliferation. Arf has been reported to suppress T-ALL development in post−b-selection thymocytes, but whether CDKN2A acts as a tumor suppressor gene in immature, pre−b-selection thymocytes remains to be elucidated. Resorting to a Rag2-deficient model of T-ALL, driven by the ETV6:: JAK2 fusion, we report that Cdkn2a haploinsufficiency at early stages of T-cell development facilitates leukemia development

2022Journal article

Open Access

Context-dependent roles for lymphotoxin-beta receptor signaling in cancer development

Publication . Fernandes, Mónica T.; Dejardin, Emmanuel; Rodrigues Dos Santos, Nuno

The LT alpha(1)beta(2) and LIGHT TNF superfamily cytokines exert pleiotropic physiological functions through the activation of their cognate lymphotoxin-beta receptor (LT beta R). Interestingly, since the discovery of these proteins, accumulating evidence has pinpointed a role for LT beta R signaling in carcinogenesis. Early studies have shown a potential anti-tumoral role in a subset of solid cancers either by triggering apoptosis in malignant cells or by eliciting an anti-tumor immune response. However, more recent studies provided robust evidence that LT beta R signaling is also involved in diverse cell-intrinsic and microenvironment-dependent pro-oncogenic mechanisms, affecting several solid and hematological malignancies. Consequently, the usefulness of LT beta R signaling axis blockade has been investigated as a potential therapeutic approach for cancer. Considering the seemingly opposite roles of LT beta R signaling in diverse cancer types and their key implications for therapy, we here extensively review the different mechanisms by which LT beta R activation affects carcinogenesis, focusing on the diverse contexts and different models assessed. (C) 2016 Elsevier B.V. All rights reserved.

2016-04Journal article

Open Access

Lymphotoxin-beta receptor and RANK signaling in TEL-JAK2-induced T-cell leukemia

Publication . Fernandes, Mónica Alexandra Teotónio; Santos, Nuno Rodrigues dos

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.

2015-09-16Doctoral thesis

Open Access