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

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is often not cured by frontline chemotherapy, and efforts to improve treatment by targeting oncogenes such as NOTCH1 have been hampered by toxicity. Silva and colleagues studied primary patient samples to show that high-level interleukin 7 receptor α ( IL7Rα) gene expression correlates with ongoing, oncogenic IL7R-mediated signaling. Using new in vivo models, they characterized the impact of IL7Rα expression on the pathogenesis of T-ALL and its response to various targeted therapies that reduce IL7-related signaling.

Key Points

• Mice overexpressing IL-7Rα develop leukemia with features of human T-ALL and sensitivity to ruxolitinib, dactolisib, and venetoclax.

• T-ALL patients with high levels of wild-type IL7R present with evidence of ongoing, oncogenic-like IL-7R–mediated activation of signaling.

Visual Abstract

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 p27 ^Kip1 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.