IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias

Ana Silva, Angelo B.A. Laranjeira, Leila R. Martins, Bruno A. Cardoso, Jocelyne Demengeot, J. Andrés Yunes, Benedict Seddon, João T. Barata

Research output: Contribution to journalArticlepeer-review

117 Citations (Scopus)

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 p27Kip1 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.
Original languageEnglish
Pages (from-to)4780 - 4789
Number of pages11
JournalCancer Research
Volume71
Issue number14
DOIs
Publication statusPublished - 15 Jul 2011
Externally publishedYes

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