Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors

• Published in: Haematologica (Roma) 2013-12, Vol.98 (12), p.1896-1904
• Main Authors: Niewerth, Denise, Franke, Niels E, Jansen, Gerrit, Assaraf, Yehuda G, van Meerloo, Johan, Kirk, Christopher J, Degenhardt, Jeremiah, Anderl, Janet, Schimmer, Aaron D, Zweegman, Sonja, de Haas, Valerie, Horton, Terzah M, Kaspers, Gertjan J L, Cloos, Jacqueline
• Format: Article
• Language: English
• Subjects: Adolescent; Boronic Acids - pharmacology; Boronic Acids - therapeutic use; Bortezomib; Child; Child, Preschool; Female; Humans; Infant; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Proteasome Endopeptidase Complex - immunology; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; Proteasome Inhibitors - therapeutic use; Protein Subunits - antagonists & inhibitors; Protein Subunits - immunology; Protein Subunits - metabolism; Pyrazines - pharmacology; Pyrazines - therapeutic use
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2013.092411

The ex vivo sensitivity of pediatric leukemia cells to the proteasome inhibitor bortezomib was compared to 3 next generation proteasome inhibitors: the epoxyketone-based irreversible proteasome inhibitors carfilzomib, its orally bio-available analog ONX 0912, and the immunoproteasome inhibitor ONX 0914. LC50 values were determined by MTT cytotoxicity assays for 29 childhood acute lymphoblastic leukemia and 12 acute myeloid leukemia patient samples and correlated with protein expression levels of the constitutive proteasome subunits (β5, β1, β2) and their immunoproteasome counterparts (β5i, β1i, β2i). Acute lymphoblastic leukemia cells were up to 5.5-fold more sensitive to proteasome inhibitors than acute myeloid leukemia cells (P