Publicação
The role of NRARP in the pathogenesis of T-cell acute lymphoblastic leukemia
| Resumo: | T-cell acute lymphoblastic leukemia (T-ALL) is a severe hematologic malignancy, commonly associated with high frequency of relapse. NOTCH signaling is a hallmark of T-ALL pathogenesis and more than 50% of T-ALL cases harbor NOTCH activating mutations. Despite considerable clinical advances throughout the years, NOTCH signaling inhibition cannot be efficiently achieved, due to weak therapeutic effects and severe toxicity. NRARP is a negative regulator of the NOTCH pathway and a transcriptional target of NOTCH. It is known to regulate both T-cell lineage commitment and early differentiation. Importantly it has been shown that in NOTCH-induced T-ALL, loss of the microRNA181ab1 inhibits T-ALL development, partly by de-repressing NRARP. NRARP further modulates WNT signaling, by stabilizing LEF1, a transcription factor acting downstream of WNT pathway, shown to induce the malignant transformation of murine thymocytes. Altogether, these findings suggest that a deregulation of NRARP function may play a role in T-ALL. Thus, the main goal of this project is to understand the role of NRARP in T-ALL pathogenesis and evaluate its therapeutic potential. We started by determining NRARP expression in human T-ALL cells. We observed that NRARP protein levels are significantly increased in T-ALL comparing with human thymocytes. This result, although consistent with the fact that NRARP is a transcriptional target of NOTCH, suggests that NRARP is not sufficient to block NOTCH oncogenic signals. To test this hypothesis, we overexpressed NRARP in human T-ALL cell lines. Intriguingly, even though we observed a block in NOTCH signaling in all cell lines analyzed, functional studies revealed that while some T-ALL cells proliferate less upon NRARP overexpression, some proliferate more. Importantly, this suppression or promotion of cell expansion correlated with the changes observed in cell cycle progression (delayed or accelerated, respectively) and cMYC expression (downregulated or upregulated, respectively) in NRARP overexpressing cells and, curiously, with the mutational status of NOTCH (mutated or wild-type, respectively). Altogether, our results suggest that NRARP is capable of blocking NOTCH signaling independently of NOTCH mutational status. Nonetheless, in T-ALL cells that depend on NOTCH oncogenic signals (NOTCH mutated cells), NRARP overexpression has a “tumor-suppressor”-like function, whereas in leukemia cells that do not depend on NOTCH oncogenic signals (NOTCH wild-type) it plays an oncogene-like role. Further studies are necessary to understand if WNT signaling contributes to this dual role of NRARP in T-ALL. |
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| Autores principais: | Pinto, Inês Garcia Brandão e Silva |
| Assunto: | T-cell acute lymphoblastic leukemia (T-ALL) NOTCH signaling WNT signaling NRARP LEF1 Teses de mestrado - 2017 |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | T-cell acute lymphoblastic leukemia (T-ALL) is a severe hematologic malignancy, commonly associated with high frequency of relapse. NOTCH signaling is a hallmark of T-ALL pathogenesis and more than 50% of T-ALL cases harbor NOTCH activating mutations. Despite considerable clinical advances throughout the years, NOTCH signaling inhibition cannot be efficiently achieved, due to weak therapeutic effects and severe toxicity. NRARP is a negative regulator of the NOTCH pathway and a transcriptional target of NOTCH. It is known to regulate both T-cell lineage commitment and early differentiation. Importantly it has been shown that in NOTCH-induced T-ALL, loss of the microRNA181ab1 inhibits T-ALL development, partly by de-repressing NRARP. NRARP further modulates WNT signaling, by stabilizing LEF1, a transcription factor acting downstream of WNT pathway, shown to induce the malignant transformation of murine thymocytes. Altogether, these findings suggest that a deregulation of NRARP function may play a role in T-ALL. Thus, the main goal of this project is to understand the role of NRARP in T-ALL pathogenesis and evaluate its therapeutic potential. We started by determining NRARP expression in human T-ALL cells. We observed that NRARP protein levels are significantly increased in T-ALL comparing with human thymocytes. This result, although consistent with the fact that NRARP is a transcriptional target of NOTCH, suggests that NRARP is not sufficient to block NOTCH oncogenic signals. To test this hypothesis, we overexpressed NRARP in human T-ALL cell lines. Intriguingly, even though we observed a block in NOTCH signaling in all cell lines analyzed, functional studies revealed that while some T-ALL cells proliferate less upon NRARP overexpression, some proliferate more. Importantly, this suppression or promotion of cell expansion correlated with the changes observed in cell cycle progression (delayed or accelerated, respectively) and cMYC expression (downregulated or upregulated, respectively) in NRARP overexpressing cells and, curiously, with the mutational status of NOTCH (mutated or wild-type, respectively). Altogether, our results suggest that NRARP is capable of blocking NOTCH signaling independently of NOTCH mutational status. Nonetheless, in T-ALL cells that depend on NOTCH oncogenic signals (NOTCH mutated cells), NRARP overexpression has a “tumor-suppressor”-like function, whereas in leukemia cells that do not depend on NOTCH oncogenic signals (NOTCH wild-type) it plays an oncogene-like role. Further studies are necessary to understand if WNT signaling contributes to this dual role of NRARP in T-ALL. |
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