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

Authors
  • Silva, Ana1, 2
  • Almeida, Afonso R M2
  • Cachucho, Ana2
  • Neto, João L2
  • Demeyer, Sofie3, 4
  • de Matos, Mafalda2
  • Hogan, Thea1
  • Li, Yunlei5
  • Meijerink, Jules6
  • Cools, Jan3
  • Grosso, Ana Rita7
  • Seddon, Benedict1
  • Barata, João T2
  • 1 Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom. , (United Kingdom)
  • 2 Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. , (Portugal)
  • 3 Vlaams Instituut voor Biotechnologie (VIB) Center for Cancer Biology.
  • 4 Katholieke Universiteit (KU) Leuven Center for Human Genetics, Katholieke Universiteit (VIB-KU) Leuven, Leuven, Belgium. , (Belgium)
  • 5 Department of Pathology Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands. , (Netherlands)
  • 6 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.; and. , (Netherlands)
  • 7 Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Unidade de Ciências Biomoleculares Aplicadas (UCIBIO), Universidade NOVA de Lisboa, Caparica, Portugal. , (Portugal)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Sep 23, 2021
Volume
138
Issue
12
Pages
1040–1052
Identifiers
DOI: 10.1182/blood.2019000553
PMID: 33970999
Source
Medline
Language
English
License
Unknown

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 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. © 2021 by The American Society of Hematology.

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