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.
| Original language | English |
|---|---|
| Pages (from-to) | 1040-1052 |
| Number of pages | 13 |
| Journal | Blood |
| Volume | 138 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 23 Sept 2021 |
Bibliographical note
Funding Information:The work was supported by the MRC under Programme Codes U117573801 and MR/P011225/1, to and by the consolidator grant ERC CoG-648455 from the European Research Council, under the European Union’s Horizon 2020 research and innovation programme, and the FAPESP/20015/2014 grant from Fundação para a Ciência e a Tecnologia (FCT) (J.T.B.). A.S. received a fellowship from FCT (SFRH/BD/18388/2004). J.T.B. was an FCT Investigator (consolidator) and A.R.G. was the recipient of an FCT Investigator grant (IF/00510/2014). This work was also supported by a grant from “Fonds Kinderen Kankervrij” (KiKa 2010-082) (Y.L.).
Funding Information:
The authors thank S. Tung and the Medical Research Council (MRC) National Institute for Medical Research Biological Services staff for assistance with mouse breeding and typing; the MRC National Institute for Medical Research flow cytometry and high-throughput sequencing core facilities; Pedro Ruivo and iMM's Comparative Pathology Unit; and Marta Fernandes for preparing the visual abstract. The work was supported by the MRC under Programme Codes U117573801 and MR/P011225/1, to and by the consolidator grant ERC CoG-648455 from the European Research Council, under the European Union's Horizon 2020 research and innovation programme, and the FAPESP/20015/2014 grant from Funda??o para a Ci?ncia e a Tecnologia (FCT) (J.T.B.). A.S. received a fellowship from FCT (SFRH/BD/18388/2004). J.T.B. was an FCT Investigator (consolidator) and A.R.G. was the recipient of an FCT Investigator grant (IF/00510/2014). This work was also supported by a grant from ?Fonds Kinderen Kankervrij? (KiKa 2010-082) (Y.L.).
Publisher Copyright:
© 2021 American Society of Hematology
