Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Notch regulated miRNAs in human T-ALL cell line

ABSTRACT: In an attempt to identify miRNAs regulated by oncogenic Notch signaling, we performed miRNA profiling of human T-cell acute lymphoblastic leukemia (T-ALL) cells with or without the treatment of γ-secretase inhibitor (GSI) to block Notch signaling. We found miR-223 levels to increase after GSI treatment suggesting that active Notch signaling represses miR-223 expression. We confirmed insulin-like growth factor-1 receptor (IGF1R) to be regulated by miR-223, but were unable to demonstrate functional effects on T-ALL cell growth by overexpression or knock-down of miR-223 alone. 4 samples analyzed, 2 cell lines each treated (GSI) and mock treated

ORGANISM(S): Homo sapiens

SUBMITTER: Andrew Weng

PROVIDER: E-GEOD-35993 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL.

Gusscott Samuel S Kuchenbauer Florian F Humphries R Keith RK Weng Andrew P AP

Leukemia research 20120317 7

To identify microRNAs regulated by oncogenic Notch signaling, we performed microarray-based miRNA profiling of T-cell acute lymphoblastic leukemia (T-ALL) cells before and after treatment with γ-secretase inhibitor (GSI) to block Notch signaling. We show miR-223 levels increase after GSI treatment suggesting that active Notch signaling represses miR-223 expression. We also demonstrate that insulin-like growth factor-1 receptor (IGF1R) is regulated by miR-223 in this context, but observe no appar ...[more]

PMID: 22424712

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Project description:Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL. Experiment Overall Design: Duplicate samples (biologic replicas) from CUTLL1 cells were treated for 24 hours with vehicle only (DMSO), dexamethasone (1microM), a gamma-secretase inhibitor (CompE 100nM) and a combination of dexamethasome plus gamma secretase inhibitor at the same concentrations indicated before. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (CompE) or the combination of both treatments.

Dataset Information

Notch regulated miRNAs in human T-ALL cell line

Publications

Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL.

Similar Datasets

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