Poster Display Malignancy and PID

OVEREXPRESSION OF WILD TYPE IL-7RΑ PROMOTES T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA

Lecture Time
10:06 - 10:07
Presenter
  • Afonso R. Almeida, Portugal
Room
Poster Area
Date
20.09.2019, Friday
Session Time
10:00 - 17:00
Board Number
5
Presentation Topic
Malignancy and PID

Abstract

Background and Aims

Background and Aims:Tight regulation of IL-7Rα expression is essential for normal T-cell development and 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 IL7RmRNA levels and cases with IL7Rgains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, on leukemogenesis remains unclear.

Methods

Methods: Overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7Rknock-in mice.

Results

Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7Rknock-in mice drives 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 p27Kip1and 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 no longer require high levels of IL-7R expression upon secondary transplantation and can progress even in the absence of IL-7, but remain sensitive to the Bcl-2 inhibitor Venetoclax. 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.

Conclusions

Conclusion: Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.

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