IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia

Interleukin-7 (IL-7), a cytokine produced in the bone marrow, thymus and other organs, is mandatory for normal human T-cell development and peripheral homeostasis. Different studies, including phase I clinical trials, have indicated the potential therapeutic value of recombinant IL-7 in the context of anti-cancer immunotherapy and as a booster of immune reconstitution. However, the two main pathways activated by IL-7, JAK/STAT5 and PI3K/Akt/mTOR, have both been implicated in cancer and there is considerable evidence that IL-7 and its receptor (IL-7R), formed by IL-7Rα (encoded by IL7R) and γc, may partake in T-cell acute lymphoblastic leukemia (T-ALL) development. In this context, the most compelling data comes from recent studies demonstrating that around 10% of T-ALL patients display IL7R gain-of-function mutations leading, in most cases, to disulfide bond-dependent homodimerization of two mutant receptors and consequent constitutive activation of downstream signaling, with ensuing cell transformation in vitro and tumorigenic ability in vivo. Here, we review the data on the involvement of IL-7 and IL-7R in T-ALL, further discussing the peculiarities of IL-7R-mediated signaling in human leukemia T-cells that may be of therapeutic value, namely regarding the potential use of PI3K and mTOR pharmacological inhibitors.