Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling by array of human T-ALL cells purified from the BM of mice treated with anti-Notch1 or control mAbs

ABSTRACT: We generated PDTALL19 xenograft by intravenously injection of primary T-ALL cells from BM of a newly diagnosed ALL pediatric patient in NOD/SCID mice. To test the effect of Notch1 blockade on PDTALL19 cells engraftment, mice were treated with anti-human Notch1 mAb OMP-52M51 (OncoMed Pharmaceuticals Inc., Redwood, CA) or control antibody (Rituximab, Roche, Basel, Switzerland) (6 mice/group). Three independent experiments (1, 2, 3) were performed. In each experiment T-ALL cells from the BM of different mice were pooled, sorted and finally RNA was extracted. Differential expression analysis identified 194 up- and 209 down-regulated genes (BH-FDR<0.05 and absolute FC>1.5) in anti-Notch1 vs. control Ab treated samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Angela Grassi

PROVIDER: E-MTAB-1349 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts.

Agnusdei V V Minuzzo S S Frasson C C Grassi A A Axelrod F F Satyal S S Gurney A A Hoey T T Seganfreddo E E Basso G G Valtorta S S Moresco R M RM Amadori A A Indraccolo S S

Leukemia 20130618 2

T-acute lymphoblastic leukemia (T-ALL) is characterized by several genetic alterations and poor prognosis in about 20-25% of patients. Notably, about 60% of T-ALL shows increased Notch1 activity, due to activating NOTCH1 mutations or alterations in the FBW7 gene, which confer to the cell a strong growth advantage. Therapeutic targeting of Notch signaling could be clinically relevant, especially for chemotherapy refractory patients. This study investigated the therapeutic efficacy of a novel anti ...[more]

PMID: 23774673

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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

Transcription profiling by array of human T-ALL cells purified from the BM of mice treated with anti-Notch1 or control mAbs

Publications

Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts.

Similar Datasets

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