| First Author | Silva A | Year | 2021 |
| Journal | Blood | Volume | 138 |
| Issue | 12 | Pages | 1040-1052 |
| PubMed ID | 33970999 | Mgi Jnum | J:314998 |
| Mgi Id | MGI:6829546 | Doi | 10.1182/blood.2019000553 |
| Citation | Silva A, et al. (2021) Overexpression of wild-type IL-7Ralpha promotes T-cell acute lymphoblastic leukemia/lymphoma. Blood 138(12):1040-1052 |
| abstractText | Tight regulation of IL-7Ralpha expression is essential for normal T-cell development. IL-7Ralpha 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-7Ralpha overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Ralpha 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-7Ralpha can promote T-cell tumorigenesis, even in the absence of IL-7Ralpha mutational activation. |
