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

| PRJNA526810 | ENA

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

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

Project description:Childhood T-cell malignancies include T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). T-ALL and T-LBL share common morphologic and immunophenotypic features and are treated with similar therapeutic approaches. Nonetheless, they show distinct clinical presentations suggesting that they may represent two different biological entities. In order to investigate the common and unique genetic aberrations of T-LBL and T-ALL, copy number alteration (CNA) analysis was performed on a subset of the samples analyzed by GEP Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from diagnostic bone marrow aspirates or tumor tissue samples. Copy number analysis of Affymetrix 100K SNP arrays was performed for 9 T-ALL and 9 T-LBL pediatric samples. The samples from leukemia/lymphoma remission were used as references for copy number inference.

2012-06-29 | E-GEOD-30319 | biostudies-arrayexpress

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

2012-06-30 | GSE30319 | 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

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Project description:T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL) and are often thought to represent a spectrum of a single disease. The malignant cells in T-ALL and T-LL are morphologically indistinguishable, and they share the expression of common cell surface antigens and cytogenetic characteristics. However, despite these similarities, differences in the predominant sites of disease in T-ALL and T-LL are observed. To determine if underlying biological distinctions may potentially contribute to some of these differences, we analyzed the global gene expression profiles of malignant T-cell precursors in ten T-ALL and nine T-LL using DNA arrays. Ten additional B-precursor ALL bone marrow samples, were used in a separate analysis. <br><br> Note that files GSM27087.txt and GSM27088.txt are identical as downloaded from GEO.

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2019-02-25 | PXD010175 | Pride

Molecular characterization of acute lymphoblastic leukemia with CRLF2 overexpression in childhood

Project description:Molecular characterization of acute lymphoblastic leukemia with CRLF2 overexpression in childhood

| PRJEB14218 | ENA

Affymetrix OncoScan SNP data for T-cell lymphoblastic lymphoma

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