High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors

Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could...

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Autores principales:	Lenka Besse, Andrej Besse, Marianne Kraus, Elmer Maurits, Herman S. Overkleeft, Beat Bornhauser, Jean-Pierre Bourquin, Christoph Driessen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	BCP-ALL T-ALL pediatric leukemia immunoproteasome proteasome inhibitors LU015i Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3cf2946c3b5a4867896f938449af3ded
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spelling	oai:doaj.org-article:3cf2946c3b5a4867896f938449af3ded2021-11-25T17:08:01ZHigh Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors10.3390/cells101128532073-4409https://doaj.org/article/3cf2946c3b5a4867896f938449af3ded2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2853https://doaj.org/toc/2073-4409Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify ALL patients responding to PI-based therapy. By using a set of activity-based proteasome probes in conjunction with cytotoxicity assays, we show that B-cell precursor ALL (BCP-ALL), in contrast to T-ALL, demonstrates an increased activity of immunoproteasome over constitutive proteasome, which correlates with high ex vivo sensitivity to the PIs bortezomib and ixazomib. The novel selective PI LU015i-targeting immunoproteasome β5i induces cytotoxicity in BCP-ALL containing high β5i activity, confirming immunoproteasome activity as a novel therapeutic target in BCP-ALL. At the same time, cotreatment with β2-selective proteasome inhibitors can sensitize T-ALL to currently available PIs, as well as to β5i selective PI. In addition, levels of total and spliced forms of XBP1 differ between BCP-ALL and T-ALL, and only in BCP-ALL does high-spliced XBP1 correlate with sensitivity to bortezomib. Thus, in BCP-ALL, high immunoproteasome activity may serve as a predictive marker for PI-based treatment options, potentially combined with XBP1 analyses.Lenka BesseAndrej BesseMarianne KrausElmer MauritsHerman S. OverkleeftBeat BornhauserJean-Pierre BourquinChristoph DriessenMDPI AGarticleBCP-ALLT-ALLpediatric leukemiaimmunoproteasomeproteasome inhibitorsLU015iBiology (General)QH301-705.5ENCells, Vol 10, Iss 2853, p 2853 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	BCP-ALL T-ALL pediatric leukemia immunoproteasome proteasome inhibitors LU015i Biology (General) QH301-705.5
spellingShingle	BCP-ALL T-ALL pediatric leukemia immunoproteasome proteasome inhibitors LU015i Biology (General) QH301-705.5 Lenka Besse Andrej Besse Marianne Kraus Elmer Maurits Herman S. Overkleeft Beat Bornhauser Jean-Pierre Bourquin Christoph Driessen High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors
description	Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify ALL patients responding to PI-based therapy. By using a set of activity-based proteasome probes in conjunction with cytotoxicity assays, we show that B-cell precursor ALL (BCP-ALL), in contrast to T-ALL, demonstrates an increased activity of immunoproteasome over constitutive proteasome, which correlates with high ex vivo sensitivity to the PIs bortezomib and ixazomib. The novel selective PI LU015i-targeting immunoproteasome β5i induces cytotoxicity in BCP-ALL containing high β5i activity, confirming immunoproteasome activity as a novel therapeutic target in BCP-ALL. At the same time, cotreatment with β2-selective proteasome inhibitors can sensitize T-ALL to currently available PIs, as well as to β5i selective PI. In addition, levels of total and spliced forms of XBP1 differ between BCP-ALL and T-ALL, and only in BCP-ALL does high-spliced XBP1 correlate with sensitivity to bortezomib. Thus, in BCP-ALL, high immunoproteasome activity may serve as a predictive marker for PI-based treatment options, potentially combined with XBP1 analyses.
format	article
author	Lenka Besse Andrej Besse Marianne Kraus Elmer Maurits Herman S. Overkleeft Beat Bornhauser Jean-Pierre Bourquin Christoph Driessen
author_facet	Lenka Besse Andrej Besse Marianne Kraus Elmer Maurits Herman S. Overkleeft Beat Bornhauser Jean-Pierre Bourquin Christoph Driessen
author_sort	Lenka Besse
title	High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors
title_short	High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors
title_full	High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors
title_fullStr	High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors
title_full_unstemmed	High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors
title_sort	high immunoproteasome activity and sxbp1 in pediatric precursor b-all predicts sensitivity towards proteasome inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3cf2946c3b5a4867896f938449af3ded
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High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors

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