Gene Set: PALOMERO_GSI_SENSITIVITY_UP

Standard name PALOMERO_GSI_SENSITIVITY_UP
Systematic name M4163
Brief description Up-regulated genes associated with sensitivity and resistance to gamma-secretase (GSI) in T-cell acute lymphoblastic leukemia (T-ALL) cell lines.
Full description or abstract Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), 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 the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 17873882   Authors: Palomero T,Sulis ML,Cortina M,Real PJ,Barnes K,Ciofani M,Caparros E,Buteau J,Brown K,Perkins SL,Bhagat G,Agarwal AM,Basso G,Castillo M,Nagase S,Cordon-Cardo C,Parsons R,Zúñiga-Pflücker JC,Dominguez M,Ferrando AA
Exact source Fig. 1a: up in sensitive & down in resistant
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Organism Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
Source platform HUMAN_GENE_SYMBOL
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