GSI-I (Z-LLNle-CHO) inhibits [gamma]-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia

• Published in: Leukemia Vol. 25; no. 7; p. 1135
• Main Authors: Meng, X, Matlawska-wasowska, K, Girodon, F, Mazel, T, Willman, C L, Atlas, S, Chen, I-m, Harvey, R C, Hunger, S P, Ness, S A, Winter, S S, Wilson, B S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-07-2011
• Subjects: Alzheimer's disease; Antibodies; Apoptosis; Biological activity; Blood & organ donations; Cancer therapies; Cell death; Diabetes; Health sciences; Leukemia; Medical prognosis; Oncology; Pediatrics; Proteins; Tumors; New Mexico; United States > US; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.50

Gamma secretase inhibitors (GSIs) comprise a growing class of compounds that interfere with the membrane-bound Notch signaling protein and its downstream intra-nuclear transcriptional targets. As GSI-I (Z-LLNle-CHO) is also a derivative of a widely used proteosome inhibitor MG-132, we hypothesized that this compound might be active in precursor-B acute lymphoblastic leukemia (ALL) cell lines and patient samples. We found that GSI-I treatment of precursor-B ALL blasts induced apoptotic cell death within 18-24h. With confirmation using RNA and protein analyses, GSI-I blocked nuclear accumulation of cleaved Notch1 and Notch2, and inhibited Notch targets Hey2 and Myc. Microarray analyses of 207 children with high-risk precursor-B ALL demonstrate that Notch pathway expression is a common feature of these neoplasms. However, microarray studies also implicated additional transcriptional targets in GSI-I-dependent cell death, including genes in the unfolded protein response, nuclear factor-κB and p53 pathways. Z-LLNle-CHO blocks both γ-secretase and proteosome activity, inducing more robust cell death in precursor-B ALL cells than either proteosome-selective or γ-secretase-selective inhibitors alone. Using Z-LLNle-CHO in a nonobese diabetes/severe combined immunodeficiency (NOD/SCID) precursor-B ALL xenograft model, we found that GSI-I alone delayed or prevented engraftment of B-lymphoblasts in 50% of the animals comprising the experimental group, suggesting that this compound is worthy of additional testing.