Display options
Cite
Besse L, Besse A, Kraus M, et al. High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors. Cells. 2021;10(11)doi: 10.3390/cells10112853.
Besse, L., Besse, A., Kraus, M., Maurits, E., Overkleeft, H. S., Bornhauser, B., Bourquin, J. P., & Driessen, C. (2021). High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors. Cells, 10(11), . https://doi.org/10.3390/cells10112853
Besse, Lenka, et al. "High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors." Cells vol. 10,11 (2021). doi: https://doi.org/10.3390/cells10112853
Besse L, Besse A, Kraus M, Maurits E, Overkleeft HS, Bornhauser B, Bourquin JP, Driessen C. High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors. Cells. 2021 Oct 22;10(11). doi: 10.3390/cells10112853. PMID: 34831075; PMCID: PMC8616377.
Copy Download .nbib Format: NLM
Share it on

Cells. 2021 Oct 22;10(11). doi: 10.3390/cells10112853.

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

Cells

Lenka Besse, Andrej Besse, Marianne Kraus, Elmer Maurits, Herman S Overkleeft, Beat Bornhauser, Jean-Pierre Bourquin, Christoph Driessen

Affiliations

  1. Department of Oncology and Hematology, Experimental Oncology and Hematology, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland.
  2. Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, 2333 CD Leiden, The Netherlands.
  3. Department of Oncology and Children's Research Centre, University Children's Hospital Zurich, 8032 Zürich, Switzerland.

PMID: 34831075 PMCID: PMC8616377 DOI: 10.3390/cells10112853

Abstract

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.

Keywords: BCP-ALL; LU015i; T-ALL; activity-based probes; immunoproteasome; pediatric leukemia; proteasome activity; proteasome inhibitors

References

  1. Semin Hematol. 2012 Jul;49(3):258-62 - PubMed
  2. Haematologica. 2015 Oct;100(10):1350-60 - PubMed
  3. Mol Cell. 1999 Sep;4(3):395-402 - PubMed
  4. Cells. 2021 Mar 17;10(3): - PubMed
  5. Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16420-16429 - PubMed
  6. Target Oncol. 2018 Dec;13(6):779-793 - PubMed
  7. Nat Methods. 2012 Jun 28;9(7):676-82 - PubMed
  8. Front Oncol. 2020 Jan 22;9:1530 - PubMed
  9. J Med Chem. 2013 Feb 14;56(3):1262-75 - PubMed
  10. PLoS One. 2017 Dec 13;12(12):e0188680 - PubMed
  11. Blood. 2012 Jul 12;120(2):285-90 - PubMed
  12. Cell Chem Biol. 2017 Feb 16;24(2):218-230 - PubMed
  13. Nature. 2001 Jul 19;412(6844):300-7 - PubMed
  14. Haematologica. 2013 Dec;98(12):1896-904 - PubMed
  15. Front Mol Biosci. 2019 Jul 16;6:48 - PubMed
  16. Blood. 2009 May 7;113(19):4667-76 - PubMed
  17. Blood. 2012 Aug 2;120(5):947-59 - PubMed
  18. Nat Immunol. 2018 Sep;19(9):923-931 - PubMed
  19. Blood Adv. 2018 Oct 9;2(19):2443-2451 - PubMed
  20. Cell Mol Life Sci. 2011 May;68(9):1491-502 - PubMed
  21. Front Mol Biosci. 2019 Mar 22;6:14 - PubMed
  22. Cell Chem Biol. 2019 Mar 21;26(3):340-351.e3 - PubMed
  23. Proc Natl Acad Sci U S A. 2014 May 27;111(21):E2219-28 - PubMed
  24. Nature. 1993 Sep 16;365(6443):264-7 - PubMed
  25. Haematologica. 2014 Feb;99(2):e14-6 - PubMed
  26. J Biol Chem. 1997 Oct 3;272(40):25200-9 - PubMed
  27. Blood. 2006 Jun 15;107(12):4907-16 - PubMed
  28. J Hematol Oncol. 2016 Sep 06;9(1):82 - PubMed
  29. Methods Enzymol. 2011;490:71-92 - PubMed
  30. J Med Chem. 2014 Jul 24;57(14):6197-209 - PubMed
  31. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10976-83 - PubMed
  32. Blood. 2017 Mar 16;129(11):e26-e37 - PubMed
  33. Angew Chem Int Ed Engl. 2016 Mar 18;55(13):4199-203 - PubMed
  34. Haematologica. 2009 Mar;94(3):419-22 - PubMed
  35. Pediatr Blood Cancer. 2014 Oct;61(10):1754-60 - PubMed

Publication Types

Grant support