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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Sep 01, 2007 |
| Title |
Gene expression analysis of gamma-secretase inhibitor-sensitive and -resistant T-ALL cell lines |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates PTEN expression and the activity of the PI3K-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with increased glycolysis and resistance to NOTCH1 inhibition in human T-ALL. These findings identify the transcriptional regulation of PTEN and the control of cellular metabolism as key elements of the oncogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.
Keywords: Drug sensitivity comparison
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| Overall design |
Samples for microarray analysis were prepared and hybridized in Affymetrix Human U133 Plus 2.0 arrays according to the manufacturer’s instructions and as previously described. RNA was extracted from duplicate cultures of GSI-sensitive (ALL-SIL, CUTLL1, DND41, HPB-ALL, KOPTK1) and GSI-resistant (CCRF-CEM, MOLT3, P12 ICHIKAWA, PF382 and RPMI8402) T-ALL cell lines treated for 24 h with vehicle (DMSO) or 500 nM CompE. Interarray intensity differences were normalized with Dchip
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| Contributor(s) |
Palomero T, Sulis M, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Mishra A, Castillo M, Basso G, Parsons R, CordonCardo C, Zúñiga-Pflücker J, Dominguez M, Ferrando AA |
| Citation(s) |
17873882 |
| Submission date |
Aug 31, 2006 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Adolfo A Ferrando |
| E-mail(s) |
af2196@columbia.edu
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| Phone |
212-851-4611
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| Organization name |
Columbia University
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| Department |
Institute for Cancer Genetics
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| Street address |
1130 St Nicholas Ave Irving Cancer Research Center 5-505A
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA96971 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE5682_RAW.tar |
117.0 Mb |
(http)(custom) |
TAR (of CEL) |
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