IL-7 Contributes to the Progression of Human T-cell Acute Lymphoblastic Leukemias

Author(s)

Silva, Ana ^{[1, 2]} ; Laranjeira, Angelo B. A. ^[3] ; Martins, Leila R. ^[1] ; Cardoso, Bruno A. ^[1] ; Demengeot, Jocelyne ^[4] ; Andres Yunes, J. ^[3] ; Seddon, Benedict ^[2] ; Barata, Joao T. ^[1]

Affiliation

^[1] Fac Med Univer, Inst Mol Med, Lisbon - Portugal

^[2] MRC Natl Inst Med Res, Div Immune Cell Biol, London - England

^[3] Ctr Infantil Boldrini, Mol Biol Lab, Campinas, SP - Brazil

^[4] Inst Gulbenkian Ciencias, Oeiras - Portugal

• Document type: Journal article
• Source: Cancer Research; v. 71, n. 14, p. 4780-4789, JUL 15 2011.
• Web of Science Citations: 57

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. Cancer Res; 71(14); 4780-9. (C) 2011 AACR. (AU)

• FAPESP's process: 08/10034-1 - Bone marrow microenvironment and PI3K pathway in resistance to chemotherapy of pediatric acute lymphoblastic leukemia
• Grantee: José Andrés Yunes
• Support Opportunities: Regular Research Grants