Author(s):
Silva, Ana Teresa ; Almeida, Afonso R. M. ; Cachucho, Ana ; Neto, João L. ; Demeyer, Sofie ; de Matos, Mafalda ; Hogan, Thea ; Li, Yunlei ; Meijerink, Jules ; Cools, Jan ; Grosso, Ana Rita ; Seddon, Benedict ; Barata, João T.
Date: 2021
Persistent ID: http://hdl.handle.net/10362/128467
Origin: Repositório Institucional da UNL
Project/scholarship:
info:eu-repo/grantAgreement/FCT/3599-PPCDT/FAPESP%2F20015%2F2014/PT;
info:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F18388%2F2004/PT;
info:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00510%2F2014%2FCP1236%2FCT0007/PT;
Subject(s): Biochemistry; Immunology; Hematology; Cell Biology; SDG 3 - Good Health and Well-being
Description
U117573801 MR/P011225/1 ERC CoG-648455 KiKa 2010-082
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.
