title: IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias.
abstract: The importance of microenvironmental factors for driving progression in leukemia has been debated. Previous evidence has pointed to interleukin-7 (IL-7), a fundamental cytokine to normal T-cell development and homeostasis, as an important determinant of the viability and proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study, we report that IL-7 is also a critical determinant of T-ALL progression. T-ALL cell lines and primary T-ALL samples initiated leukemia more slowly when engrafted to immunocompromised Rag2(-/-)IL2rg(-/-) mice lacking IL-7. This effect was not related to reduced engraftment or homing of transplanted cells to the bone marrow. Instead, IL-7 deficiency diminished expansion of leukemia cells in the bone marrow and delayed leukemia-associated death of transplanted mice. Moreover, infiltration of different organs by T-ALL cells, which characterizes patients with advanced disease, was more heterogeneous and generally less efficient in IL-7-deficient mice. Leukemia progression was associated with increased Bcl-2 expression and cell viability, reduced p27(Kip1) expression, and decreased cell-cycle progression. Clinical measurements of IL-7 plasma levels and IL-7 receptor (IL-7R) expression in T-ALL patients versus healthy controls confirmed that IL-7 stimulates human leukemia cells. Our results establish that IL-7 contributes to the progression of human T-cell leukemia, and they offer preclinical validation of the concept that targeting IL-7/IL-7R signaling in the tumor microenvironment could elicit therapeutic effects in T-ALL.
authors: Instituto de Medicina Molecular, Faculdade de Medicina da Univer, Lisbon, Portugal.
authors: Ana
authors: A
authors: Silva
authors: Angelo B A
authors: AB
authors: Laranjeira
authors: Leila R
authors: LR
authors: Martins
authors: Bruno A
authors: BA
authors: Cardoso
authors: Jocelyne
authors: J
authors: Demengeot
authors: J Andrés
authors: JA
authors: Yunes
authors: Benedict
authors: B
authors: Seddon
authors: João T
authors: JT
authors: Barata