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

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 expr...

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Autores principales:	Tyler W. Jenkins, Sondra L. Downey-Kopyscinski, Jennifer L. Fields, Gilbert J. Rahme, William C. Colley, Mark A. Israel, Andrey V. Maksimenko, Steven N. Fiering, Alexei F. Kisselev
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f287ffb014d44282a148d0dbf994ac53
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spelling	oai:doaj.org-article:f287ffb014d44282a148d0dbf994ac532021-12-02T15:00:59ZActivity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein10.1038/s41598-021-90451-92045-2322https://doaj.org/article/f287ffb014d44282a148d0dbf994ac532021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90451-9https://doaj.org/toc/2045-2322Abstract 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.Tyler W. JenkinsSondra L. Downey-KopyscinskiJennifer L. FieldsGilbert J. RahmeWilliam C. ColleyMark A. IsraelAndrey V. MaksimenkoSteven N. FieringAlexei F. KisselevNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tyler W. Jenkins Sondra L. Downey-Kopyscinski Jennifer L. Fields Gilbert J. Rahme William C. Colley Mark A. Israel Andrey V. Maksimenko Steven N. Fiering Alexei F. Kisselev Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein
description	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.
format	article
author	Tyler W. Jenkins Sondra L. Downey-Kopyscinski Jennifer L. Fields Gilbert J. Rahme William C. Colley Mark A. Israel Andrey V. Maksimenko Steven N. Fiering Alexei F. Kisselev
author_facet	Tyler W. Jenkins Sondra L. Downey-Kopyscinski Jennifer L. Fields Gilbert J. Rahme William C. Colley Mark A. Israel Andrey V. Maksimenko Steven N. Fiering Alexei F. Kisselev
author_sort	Tyler W. Jenkins
title	Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein
title_short	Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein
title_full	Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein
title_fullStr	Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein
title_full_unstemmed	Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein
title_sort	activity of immunoproteasome inhibitor onx-0914 in acute lymphoblastic leukemia expressing mll–af4 fusion protein
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f287ffb014d44282a148d0dbf994ac53
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Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein

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