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

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

PROVIDER: PRJNA526810 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8718350_1.fastq.gz	Fastqsanger.gz
	SRR8718350_2.fastq.gz	Fastqsanger.gz
	SRR8718351_1.fastq.gz	Fastqsanger.gz
	SRR8718351_2.fastq.gz	Fastqsanger.gz
	SRR8718352_1.fastq.gz	Fastqsanger.gz

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

Project description: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 T-ALL patients display very high IL7R mRNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, on leukemogenesis remains unclear. Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knock-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 p27Kip1 and 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. Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.

2021-09-07 | GSE128212 | GEO

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

Project description: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.

| S-EPMC8462360 | biostudies-literature

Affymetrix SNP array data for acute lymphoblastic leukemia and lymphoblastic lymphoma samples

2012-06-30 | GSE30319 | GEO

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miRNA profiling of pediatric T cell lymphoblastic lymphoma

Project description:miRNA profiling has been performed on primary tumor samples collected at diagnosis from pediatric patients affected by T-cell lymphoblastic lymphoma.

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Project description:microRNA profiling of T-cell lymphoblastic lymphoma vs fetal thymus

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