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

X Meng; K Matlawska-Wasowska; F Girodon; T Mazel; C L Willman; S Atlas; I-M Chen; R C Harvey; S P Hunger; S A Ness; S S Winter; B S Wilson

doi:10.1038/leu.2011.50

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

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

X Meng, K Matlawska-Wasowska, F Girodon, T Mazel, C L Willman, S Atlas, I-M Chen, R C Harvey, S P Hunger, S A Ness, …

Leukemia, Vol.25(7), pp.1135-1146

07/2011

DOI: 10.1038/leu.2011.50

PMCID: PMC3170956

PMID: 21494254

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Abstract

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 18–24 h. 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.

gamma secretase inhibitor

Notch

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precursor-B acute lymphoblastic leukemia

proteosome

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Title: Subtitle: GSI-I (Z-LLNle-CHO) inhibits γ-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia
Creators: X Meng - University of New Mexico Hospital
K Matlawska-Wasowska - , Albuquerque, NM
F Girodon - University of New Mexico Hospital
T Mazel - University of New Mexico Hospital
C L Willman - University of New Mexico Hospital
S Atlas - University of New Mexico Hospital
I-M Chen - University of New Mexico Hospital
R C Harvey - University of New Mexico Hospital
S P Hunger - University of Colorado Denver
S A Ness - University of New Mexico Hospital
S S Winter - University of New Mexico Hospital
B S Wilson - University of New Mexico Hospital
Resource Type: Journal article
Publication Details: Leukemia, Vol.25(7), pp.1135-1146
DOI: 10.1038/leu.2011.50
PMID: 21494254
PMCID: PMC3170956
NLM abbreviation: Leukemia
ISSN: 0887-6924
eISSN: 1476-5551
Publisher: Nature Publishing Group
Alternative title: GSI-I kills precursor-B ALL cells
Language: English
Date published: 07/2011
Academic Unit: Pathology
Record Identifier: 9984186407702771

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