RSS Cientifico geral Exploring new facets of interleukin-7 receptor-mediated signaling in T-cell leukemia

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Breve resumo:
Acute Lymphoblastic Leukemia (ALL) is the most common childhood malignancy with 15% of children and 25% of adult ALL cases presenting with a T-cell phenotype (TALL), which is associated with higher risk and poorer prognosis. Interleukin-7 (IL-7) is a cytokine crucial for normal T-cell development. However, IL-7 and its receptor (IL-7R) can also partake in T-cell leukemia. In fact, it was previously described that around 10% of T-ALL patients display gain-of-function mutations in the IL7R gene (that codes for IL-7R伪). These mutations promote homodimerization of the receptor and consequent ligand-independent constitutive activation of the downstream pathways (namely JAK/STAT and PI3K/Akt/mTOR) leading to cell transformation in vitro and tumorigenic ability in vivo. The non-requirement for the ligand brings up the possibility of the mutant receptor being able to signal from intracellular compartments, even before reaching the plasma membrane, which could provide leukemic cells an evasion strategy towards a possible IL-7R targeted therapy. The current thesis pretends to tackle this hypothesis by first determining whether the mutant receptor has intracellular activity and then by defining the exact location from which this putative activity occurs. Our results indicate that intracellularly located mutant IL-7R is capable of promoting cell viability through the activation of its associated downstream pathways. To try to identify the location in which this process occurs, the current work explored the possibility of the receptor promoting downstream signaling from the endoplasmic reticulum (ER). By using the method of retention using selective hooks (RUSH) it was possible to establish preliminary results suggesting that the mutant receptor has some activity in this compartment, although not optimal. Altogether our results suggest that the mutant IL-7R is capable of promoting signaling form within the cell, in part from the ER and possibly somewhere along the trafficking route between this organelle and the plasma membrane.​



Info Adicional:
Acute Lymphoblastic Leukemia (ALL) is the most common childhood malignancy with 15% of children and 25% of adult ALL cases presenting with a T-cell phenotype (TALL), which is associated with higher risk and poorer prognosis. Interleukin-7 (IL-7) is a cytokine crucial for normal T-cell development. However, IL-7 and its receptor (IL-7R) can also partake in T-cell leukemia. In fact, it was previously described that around 10% of T-ALL patients display gain-of-function mutations in the IL7R gene (that codes for IL-7R伪). These mutations promote homodimerization of the receptor and consequent ligand-independent constitutive activation of the downstream pathways (namely JAK/STAT and PI3K/Akt/mTOR) leading to cell transformation in vitro and tumorigenic ability in vivo. The non-requirement for the ligand brings up the possibility of the mutant receptor being able to signal from intracellular compartments, even before reaching the plasma membrane, which could provide leukemic cells an evasion strategy towards a possible IL-7R targeted therapy. The current thesis pretends to tackle this hypothesis by first determining whether the mutant receptor has intracellular activity and then by defining the exact location from which this putative activity occurs. Our results indicate that intracellularly located mutant IL-7R is capable of promoting cell viability through the activation of its associated downstream pathways. To try to identify the location in which this process occurs, the current work explored the possibility of the receptor promoting downstream signaling from the endoplasmic reticulum (ER). By using the method of retention using selective hooks (RUSH) it was possible to establish preliminary results suggesting that the mutant receptor has some activity in this compartment, although not optimal. Altogether our results suggest that the mutant IL-7R is capable of promoting signaling form within the cell, in part from the ER and possibly somewhere along the trafficking route between this organelle and the plasma membrane.



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