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Title:
GSI-I (Z-LLNle-CHO) inhibits γ-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia | Leukemia
Description:
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.
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Hematology
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name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:C L Willman
affiliation:
name:University of New Mexico Health Sciences Center
address:
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:The UNM Cancer Center, University of New Mexico Health Sciences Center
address:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:S Atlas
affiliation:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center
address:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:University of New Mexico Health Sciences Center
address:
name:Department of Physics, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:I-M Chen
affiliation:
name:University of New Mexico Health Sciences Center
address:
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:The UNM Cancer Center, University of New Mexico Health Sciences Center
address:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:R C Harvey
affiliation:
name:University of New Mexico Health Sciences Center
address:
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:The UNM Cancer Center, University of New Mexico Health Sciences Center
address:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:S P Hunger
affiliation:
name:The Children's Hospital and the University of Colorado Denver School of Medicine
address:
name:Department of Pediatrics, The Children's Hospital and the University of Colorado Denver School of Medicine, Aurora, USA
type:PostalAddress
type:Organization
name:S A Ness
affiliation:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center
address:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:University of New Mexico Health Sciences Center
address:
name:Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:S S Winter
affiliation:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center
address:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:University of New Mexico Health Sciences Center
address:
name:Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
email:[email protected]
name:B S Wilson
affiliation:
name:University of New Mexico Health Sciences Center
address:
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
name:The UNM Cancer Center, University of New Mexico Health Sciences Center
address:
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
type:PostalAddress
type:Organization
PostalAddress:
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:8Current address: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.,
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Laboratoire dâHématologie, Centre Hospitalier Universitaire de Dijon, Dijon, France
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Physics, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Pediatrics, The Children's Hospital and the University of Colorado Denver School of Medicine, Aurora, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, USA
name:Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA
name:The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
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