Cooperación funcional de notch1 e il-7r en el desarrollo de los linfocitos t humanos y en la fisiopatología de la leucemia t linfoblástica aguda

• Autores: Sara González García
• Directores de la Tesis: María Luisa Toribio García (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2011
• Idioma: español
• Tribunal Calificador de la Tesis: Balbino Jose Alarcon Sanchez (presid.), José Felix de Celis Ibeas (secret.), Almudena Rodríguez Ramiro (voc.), María Luisa Gaspar Alonso-Vega (voc.), José Luis de la Pompa Mínguez (voc.)
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: digitool-uam.greendata.es
• Resumen

  • The development of T lymphocytes from hematopoietic stem cells within the thymus is a tightly regulated process guided by inductive signals provided by the thymic microenvironment. Among these signals are those provided by interaction between the Notch1 receptor and its Delta-like ligands expressed on the surface of thymic epithelial cells. This interaction is an initial obligatory event for the earliest lymphomyeloid progenitors seeding the thymus to enter the T-cell differentiation program. Once a progenitor commits to the T-cell lineage, its proliferation and survival is highly dependent on growth signals derived from the interleukin 7 receptor (IL-7R). The mechanism responsible for the dynamic- and lineage-specific expression of IL-7R during thymopoiesis remained unknown, although different transcription factors, such PU.1 and GABP¿, were found to regulate expression of the gene encoding the IL-7R alpha chain (IL7R) during B-cell development, and the later also regulates IL7R transcription in mature T-cells.

    In this study we show that Notch1 signaling is responsible for the stage- and lineage-specific expression of IL-7R¿ during human intrathymic T-cell development, thus controlling the IL-7-dependent expansion of the T-cell progenitor pool prior to ß-selection maturation stage. We also demonstrate that Notch dependent regulation of IL-7R¿ expression is common to T-cell acute lymphoblastic leukemias (T-ALL), where activating mutations of Notch1 are found in more than 60% of the patients.

    Because IL-7R signaling was found to rescue cell proliferation in Notch-deprived TALLs, next we addressed the contribution of IL-7R to T-ALL oncogenesis. We show that expression of IL-7R¿ is necessary to support not only T- but also pre-B-ALL proliferation in vitro. More importantly, it is critically required for tumor development of ALLs in vivo. Although no oncogenic mutations were identified in IL7R that supported the observed IL-7R dependency of ALLs, this can be explained by the existence of a positive feed-back loop between IL-7R and Notch signaling pathways. In fact, IL-7R is able to promote Notch1 activation by inducing ADAM metalloproteases function in an ERK1/2-dependent fashion.

    In summary, we describe a new cross-regulation between the two main pathways implicated in T-cell development, which are also activated in T-ALLs, opening new opportunities for the design of targeted therapies against this type of cancer.