Alteraciones de la expresión y la fosforilación de FADD en linfoma linfoblástico de células T

• Autores: José Luís Marín Rubio
• Directores de la Tesis: José Fernández Piqueras (dir. tes.), María Villa Morales (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019
• Idioma: español
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Biología molecular
  • Ciencias médicas
    • Medicina interna
      • Hematología
    • Patología
      • Oncología
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• Resumen

  • T-cell lymphoblastic neoplasms are aggressive haematological malignancies which mainly develop in children but can also affect adults. The molecular basis of T-cell lymphoblastic lymphoma is not fully understood. In consequence, there is a lack of robust and reliable prognostic markers, thus hindering the achievement of better results in the clinic. The role of FADD in cancer is controversial, probably due to its dual role in apoptosis and other non-apoptotic functions such as proliferation and cell cycle control. Moreover, it seems that these non-canonical functions depend on FADD phosphorylation and subcellular location. Despite FADD having a relevant role in T cells, alterations affecting its expression and phosphorylation are not completely unveiled in haematological cancers. In the present work, we show that T-cell lymphoblastic lymphoma cells exhibit a significant reduction of FADD, both in mouse and human. The proteomic approach indicates that FADD reduction in tumour T cells impacts on mitochondrial processes as well as in the regulation of messenger RNA processing and maturation. However, apoptosis impairment due to FADD reduction is probably the main FADD-mediated oncogenic event in T-LBL tumour cells. Nevertheless, the phosphorylation status of the remaining FADD protein is capable of shaping its non-apoptotic functions. Phosphorylated FADD is significantly reduced as well in T-cell lymphoblastic lymphoma. Even though, phosphorylated FADD is more stable and more prone to be nuclear. There, it would be prevented from participating in death receptors- mediated apoptosis and it would favour tumour cell proliferation. Interestingly, we have determined that the level of FADD phosphorylation can provide the basis for patient stratification. Higher levels of phosphorylated FADD in the tumour significantly correlate with shorter survival times in mice and with worse clinical prognosis in human patients. This supports that FADD phosphorylation status may serve as a predictor for aggressiveness and tumour outcome. In summary, we propose FADD phosphorylation as a new biomarker with prognostic value in T-cell lymphoblastic lymphoma.