Original Article

Leukemia (2011) 25, 1135–1146; doi:10.1038/leu.2011.50; published online 15 April 2011

Acute Leukemias

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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X Meng1,2,8,10, K Matlawska-Wasowska1,2,10, F Girodon1,3, T Mazel1, C L Willman1,2, S Atlas2,4, I-M Chen1,2, R C Harvey1,2, S P Hunger5,9, S A Ness2,6, S S Winter2,7 and B S Wilson1,2

  1. 1Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
  2. 2The UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
  3. 3Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Dijon, Dijon, France
  4. 4Department of Physics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
  5. 5Department of Pediatrics, The Children's Hospital and the University of Colorado Denver School of Medicine, Aurora, CO, USA
  6. 6Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
  7. 7Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

Correspondence: Dr SS Winter, T John Gribble Endowed Chair, Pediatric Hematology/Oncology, MSC 10 5590, 1 University of New Mexico, Albuquerque, NM 87131, USA. E-mail: swinter@salud.unm.edu

8Current address: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.

9Ergen Family Chair in Pediatric Cancer.

10These authors contributed equally to this work.

Received 24 March 2009; Revised 7 January 2011; Accepted 17 February 2011; Published online 15 April 2011.

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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 18–24h. 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.

Keywords:

precursor-B acute lymphoblastic leukemia; gamma secretase inhibitor; Notch; proteosome