Silva, AP;
Almeida, ARM;
Cachucho, A;
Neto, JL;
Demeyer, S;
Ramos de Matos, M;
Hogan, T;
... Barata, JT; + view all
(2021)
Overexpression of wild type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma.
Blood
, 138
(12)
pp. 1040-1052.
10.1182/blood.2019000553.
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Abstract
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 T-ALL patients display very high IL7R mRNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, on leukemogenesis remains unclear. Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knock-in mice drives potential thymocyte self-renewal, and thymus hyperplasia due to increased proliferation of T-cell precursors, which subsequently infiltrate lymph nodes, spleen and bone marrow, ultimately leading to fatal leukemia. The tumors mimic key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of PI3K/Akt pathway that is paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing JAK/STAT, PI3K/Akt/mTOR and Notch signaling activation. Notably, we also find that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and can progress 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 T-ALL patient samples with high wild type IL7R expression display a transcriptional signature resembling that from IL-7-stimulated pro-T cells and, critically, from IL7R mutant T-ALL cases. Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.
Type: | Article |
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Title: | Overexpression of wild type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1182/blood.2019000553 |
Publisher version: | https://doi.org/10.1182/blood.2019000553 |
Language: | English |
Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
Keywords: | adult t-cell lymphoma/leukemia, lymphoma, protein overexpression, t-cell leukemia, acute, interleukin 7 receptor, leukemia, ruxolitinib, venetoclax, 1-phosphatidylinositol 3-kinase, mtor serine-threonine kinases |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
URI: | https://discovery.ucl.ac.uk/id/eprint/10128063 |
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