2. Academic Validation
  3. Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein

Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein

  • Sci Rep. 2021 May 25;11(1):10883. doi: 10.1038/s41598-021-90451-9.
Tyler W Jenkins 1,  Sondra L Downey-Kopyscinski 2 3 4 5 6 7 8,  Jennifer L Fields 2 9,  Gilbert J Rahme 2 3 4 5 6 7 8,  William C Colley 1 4 5 6 7 8,  Mark A Israel 2 9 4 5 6 7 8,  Andrey V Maksimenko 1,  Steven N Fiering 2 9,  Alexei F Kisselev 10
Affiliations

Affiliations

  • 1 Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, PRB, 720 S. Donahue Dr., Auburn, AL, 36849, USA.
  • 2 Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
  • 3 Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
  • 4 SLDK - Rancho Biosciences, San Diego, CA, USA.
  • 5 GJR- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 7 WCC - ScribeAmerica, Huntsville Hospital, Huntsville, AL, USA.
  • 8 MAI- Israel Cancer Research Fund, New York, NY, USA.
  • 9 Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
  • 10 Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, PRB, 720 S. Donahue Dr., Auburn, AL, 36849, USA. AFK0006@auburn.edu.
PMID: 34035431 DOI: 10.1038/s41598-021-90451-9
Abstract

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL-AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to Proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL-AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of Proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL.

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