IL-7- AND PI3K-MEDIATED SIGNALING IN T-CELL LEUKEMIA: THE ROLE OF EXTERNAL AND CELL-AUTONOMOUS SIGNALS IN TUMORIGENESIS

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Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma

Publication . Silva, Ana; Almeida, Afonso; Cachucho, Ana; Neto, João Luís; Demeyer, Sofie; Ramos De Matos, Mafalda; Hogan, Thea; Li, Yunlei; Meijerink, Jules; Cools, Jan; Grosso, Ana Rita; Seddon, Benedict; Barata, João T.

Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK/STAT, PI3K/Akt/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K/mTOR), palbociclib (Cdk4/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7-stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7Rα can promote T-cell tumorigenesis, even in the absence of IL-7Rα mutational activation.

2021Journal article

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Molecular and functional evidence for activity of murine IL-7 on human lymphocytes

Publication . Barata, João T.; Silva, Ana; Abecasis, Miguel; Carlesso, Nadia; Cumano, Ana; Cardoso, Angelo A.

Although interleukin-7 (IL-7) is essential for human and murine lymphopoiesis and homeostasis, clear disparities between these species regarding the role of IL-7 during B-cell development suggest that other, subtler differences may exist. One basic unsolved issue of IL-7 biology concerns cross-species activity, because in contrast to the human ortholog, the ability of murine (m)IL-7 to stimulate human cells remains unresolved. Establishing whether two-way cross-species reactivity occurs is fundamental for evaluating the role of IL-7 in chimeric human-mouse models, which are the most versatile tools for studying human lymphoid development and disease in vivo. Here, we show that mIL-7 triggers the same signaling pathways as human (h)IL-7 in human T cells, promoting similar changes in viability, proliferation, size, and immunophenotype, even at low concentrations. This ability is not confined to T cells, because mIL-7 mediates cell growth and protects human B-cell precursors from dexamethasone-induced apoptosis. Importantly, endogenous mIL-7 produced in the mouse thymic microenvironment stimulates human T cells, because their expansion in chimeric fetal thymic organ cultures is inhibited by a mIL-7-specific neutralizing antibody. Our results demonstrate that mIL-7 affects human lymphocytes and indicate that mouse models of human lymphoid development and disease must integrate the biological effects of endogenous IL-7 on human cells.

2006Journal article

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