Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression profiling of mouse T-ALL (Vav-tTA;TRE-GFP-shIkaros primary leukemia ALL101) cells following Ikaros restoration [RNA-Seq]

ABSTRACT: To examine Ikaros tumor suppressor mechanisms, we have utilized inducible RNAi to dynamically restore endogenous Ikaros expression in T-ALL driven by its knockdown. This causes rapid transcriptional repression of Notch1 and associated targets including Myc, even in leukemias harboring spontaneous activating Notch1 mutations (producing aberrant ICN1) similar to those found in 60% of human T-ALL. Ikaros restoration results in sustained regression of Notch1-wild type leukemias while endogenous or engineered ICN1 expression promotes rapid disease relapse, indicating that ICN1 functionally antagonizes Ikaros in T-ALL. RNA-seq was performed on T-ALL (Vav-tTA;TRE-GFP-shIkaros primary leukemia ALL101) cells isolated from three untreated and three 3-day Dox-treated mice. There were two sequencing runs of each RNA sample.

ORGANISM(S): Mus musculus

SUBMITTER: Gordon Smyth

PROVIDER: E-GEOD-54447 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia.

Witkowski M T MT Cimmino L L Hu Y Y Trimarchi T T Tagoh H H McKenzie M D MD Best S A SA Tuohey L L Willson T A TA Nutt S L SL Busslinger M M Aifantis I I Smyth G K GK Dickins R A RA

Leukemia 20150206 6

Activating NOTCH1 mutations occur in ~60% of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in ~5% of cases. To investigate the regulatory interplay between these driver genes, we have used a novel transgenic RNA interference mouse model to produce primary T-ALLs driven by reversible Ikaros knockdown. Restoring endogenous Ikaros expression in established T-ALL in vivo acutely represses Notch1 and its oncogenic target ge ...[more]

PMID: 25655195

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Project description:Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice.

Dataset Information

Expression profiling of mouse T-ALL (Vav-tTA;TRE-GFP-shIkaros primary leukemia ALL101) cells following Ikaros restoration [RNA-Seq]

Publications

Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia.

Similar Datasets

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