IntroductionNotch proteins are a family of ligand-activated large (300 kDa) single-pass transmembrane heterodimeric receptors. 1 Notch controls multiple cell fate decisions and differentiation processes during lymphocyte development and function and is required at various stages of T-cell development. 2,3 Deregulated Notch signaling during T-cell development leads to malignant transformation, including the cancer most closely associated with aberrant Notch expression in humans, acute T-cell acute lymphoblastic leukemia (T-ALL), which constitutes approximately 15% to 20% of ALLs seen in adults and children. 4,5 The oncogenic potential of Notch was first identified in (t7;9) chromosomal rearrangement in approximately 2% of human T-ALL, whereby intracelluar Notch1 is translocated to the T-cell receptor (TCR) ␤ gene. 6 More than 50% of human T-ALLs bear mutations in Notch1, indicating a prominent role for Notch in this T-cell malignancy. 7 Inhibitors of Notch signaling abrogate the growth of human and murine T-ALL cell lines bearing Notch1 gain-of-function mutations, indicating Notch is required in established tumors. 8,9 In vertebrates, 4 notch receptors (Notch 1-4) are activated by 5 different Notch ligands expressed on various cell types: Jagged1, Jagged2, and Delta-like (DL)1, DL3, and DL4. 2,3 After ligandbinding, proteolytic cleavage by ␥-secretase releases the signalingcompetent intracellular domain of Notch (N IC ). 10-12 N IC is composed of a RAM domain, ankyrin repeats (ANK) that mediate protein-protein interactions, nuclear localization sequences, a transactivation domain (TAD), and a C-terminal PEST domain regulating protein turnover. Human T-ALL cases frequently bear activating mutations in the extracellular heterodimerization domain and/or the C-terminal PEST domain of Notch1, resulting in ligand-independent activation. 7 During canonical Notch signaling, N IC translocates to the nucleus, engages its nuclear binding protein CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans) and transcribes downstream target genes, including the HES family of transcriptional repressors. 13,14 In the absence of N IC , CSL recruits repressor complexes to the regulatory regions of Notch/CSL target genes, inhibiting transcription. N IC interaction with CSL acts as a switch that promotes the assembly of CSL coactivator complexes. [15][16][17] ␥-Secretase inhibitors (GSIs) block proteolytic cleavage of Notch receptors, thereby preventing activation of Notch. Use of GSI in activated T cells results in down-regulation of nuclear factor (NF)-B activity, cytokine (interleukin-2 [IL-2] and interferon-␥ [IFN-␥]) production, and cell proliferation. 18 In T-cell lymphomas, context-specific putative target genes have been identified through which Notch1 may promote transformation by altering cell-growth kinetics. [19][20][21] The D-type cyclins (cyclins D1, D2, and D3) are the first cyclins to be induced as cells enter the G 1 phase of the cell cycle, [22][23][24] and, thus, if regulat...

K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation in murine models is sufficient to recapitulate the spectrum of lesions seen in human pancreatic ductal adenocarcinoma