Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy

Authors: Denise Niewerth, Gertjan J. L. Kaspers, Gerrit Jansen, Johan van Meerloo, Sonja Zweegman, Gaye Jenkins, James A. Whitlock, Stephen P. Hunger, Xiaomin Lu, Todd A. Alonzo, Peter M. van de Ven, Terzah M. Horton, Jacqueline Cloos

Published in: Journal of Hematology & Oncology | Issue 1/2016

Login to get access

Abstract

Background

Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL).

Methods

We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1) and AML (COG-AAML07P1). Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12) obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test.

Results

Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001). These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028) between patients who did (n = 4) and did not reach complete remission (CR) (n = 8), although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples.

Conclusions

These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.
Appendix
Available only for authorised users
Literature
1.
Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120:1165–74.CrossRefPubMedPubMedCentral
2.
3.
Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120:947–59.CrossRefPubMedPubMedCentral
4.
Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24:4867–74.CrossRefPubMed
5.
Horton TM, Gannavarapu A, Blaney SM, D’Argenio DZ, Plon SE, Berg SL. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother Pharmacol. 2006;58:13–23.CrossRefPubMed
6.
Houghton PJ, Morton CL, Kolb EA, Lock R, Carol H, Reynolds CP, et al. Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50:37–45.CrossRefPubMed
7.
Horton TM, Perentesis JP, Gamis AS, Alonzo TA, Gerbing RB, Ballard J, et al. A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia : a report from the children’s oncology group. Pediatr Blood Cancer. 2014;61:1754–60.CrossRefPubMedPubMedCentral
8.
Messinger YH, Gaynon PS, Sposto R, van der GJ, Eckroth E, Malvar J, et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood. 2012;120:285–90.CrossRefPubMed
9.
Groettrup M, Kirk CJ, Basler M. Proteasomes in immune cells: more than peptide producers? Nat Rev Immunol. 2010;10:73–8.CrossRefPubMed
10.
Niewerth D, Franke NE, Jansen G, Assaraf YG, van Meerloo J, Kirk CJ, et al. Higher ratio immune vs. constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. Haematologica. 2013;98:1896–904.CrossRefPubMedPubMedCentral
11.
Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, Lorens JB, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009;114:3439–47.CrossRefPubMed
12.
Basler M, Kirk CJ, Groettrup M. The immunoproteasome in antigen processing and other immunological functions. Curr Opin Immunol. 2012;25:74–80.CrossRefPubMed
13.
Obeng EA, Carlson LM, Gutman DM, Harrington WJ, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–16.CrossRefPubMedPubMedCentral
14.
McConkey DJ, Zhu K. Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist. 2008;11:164–79.CrossRef
15.
Horton TM, Pati D, Plon SE, Thompson PA, Bomgaars LR, Adamson PC, et al. A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children’s Oncology Group study. Clin Cancer Res. 2007;13:1516–22.CrossRefPubMed
16.
Cortes J, Thomas D, Koller C, Giles F, Estey E, Faderl S, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res. 2004;10:3371–6.CrossRefPubMed
17.
Faderl S, Rai K, Gribben J, Byrd JC, Flinn IW, O’Brien S, et al. Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. Cancer. 2006;107:916–24.CrossRefPubMed
18.
Santos FP, Kantarjian H, McConkey D, O’Brien S, Faderl S, Borthakur G, et al. Pilot study of bortezomib for patients with imatinib-refractory chronic myeloid leukemia in chronic or accelerated phase. Clin Lymphoma Myeloma Leuk. 2011;11:355–60.CrossRefPubMedPubMedCentral
19.
Minderman H, Zhou Y, O’Loughlin KL, Baer MR. Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Cancer Chemother Pharmacol. 2007;60:245–55.CrossRefPubMed
20.
Attar EC, De Angelo DJ, Supko JG, D’Amato F, Zahrieh D, Sirulnik A, et al. Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia. Clin Cancer Res. 2008;14:1446–54.CrossRefPubMed
21.
Blum W, Schwind S, Tarighat SS, Geyer S, Eisfeld AK, Whitman S, et al. Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia. Blood. 2012;119:6025–31.CrossRefPubMedPubMedCentral
22.
Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood. 2005;105:3058–65.CrossRefPubMed
23.
Brown RE, Bostrom B, Zhang PL. Morphoproteomics and bortezomib/dexamethasone-induced response in relapsed acute lymphoblastic leukemia. Ann Clin Lab Sci. 2004;34:203–5.PubMed
24.
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149–57.CrossRefPubMed
25.
Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJL, Cloos J. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat. 2015;18:18–35.CrossRefPubMed
26.
Niewerth D, Kaspers GJL, Assaraf YG, van Meerloo J, Kirk CJ, Anderl JA, et al. Interferon-y-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines. J Hematol Oncol. 2014;7.
27.
Franke NE, Niewerth D, Assaraf YG, Van Meerloo J, Vojtekova K, van Zantwijk CH, et al. Impaired bortezomib binding to mutant beta5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia. 2012;26:757–68.CrossRefPubMed
28.
Blackburn C, Gigstad KM, Hales P, Garcia K, Jones M, Bruzzese FJ, et al. Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit. Biochem J. 2010;430:461–76.CrossRefPubMedPubMedCentral
29.
Cloos J, Niewerth D, Jansen G. Pre-clinical studies on the molecular basis of bortezomib resistance and modalities to overcome resistance in hematological malignancies. In: Dou QP, ed. Resist. to proteasome Inhib. cancer. Switzerland: Springer International Publishing Switzerland; 2014. p. 181–204.
30.
Cottini F, Guidetti A, Paba Prada C, Hideshima T, Maglio M, Varga D, et al. Resistance to proteasome inhibitors in multiple myeloma. In: Dou QP, ed. Resist. to Proteasome Inhib. Cancer. Switzerland: Springer International Publishing Switzerland; 2014. p. 47–80.
31.
Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. 2008;112:2489–99.CrossRefPubMed
32.
Politou M, Karadimitris A, Terpos E, Kotsianidis I, Apperley JF, Rahemtulla A. No evidence of mutations of the PSMB5 (beta-5 subunit of proteasome) in a case of myeloma with clinical resistance to Bortezomib. Leuk Res. 2006;30:240–1.CrossRefPubMed
33.
Shuqing L, Jianmin Y, Chongmei H, Hui C, Wang J. Upregulated expression of the PSMB5 gene may contribute to drug resistance in patient with multiple myeloma when treated with bortezomib-based regimen. Exp Hematol. 2011;39:1117–8.CrossRefPubMed
34.
Lichter DI, Danaee H, Pickard MD, Tayber O, Sintchak M, Shi H, et al. Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone. Blood. 2012;120:4513–6.CrossRefPubMedPubMedCentral
35.
Lu S, Chen Z, Yang J, Chen L, Gong S, Zhou H, et al. Overexpression of the PSMB5 gene contributes to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line. Exp Hematol. 2008;36:1278–84.CrossRefPubMed
36.
de Bruin G, Xin BT, Kraus M, van der Stelt M, van der Marel GA, Kisselev AF, et al. A set of activity-based probes to visualize human (immuno)proteasome activities. Angew Chem Int Ed Engl. 2016;55:4199–203.CrossRefPubMed
37.
Busse A, Kraus M, Na IK, Rietz A, Scheibenbogen C, Driessen C, et al. Sensitivity of tumor cells to proteasome inhibitors is associated with expression levels and composition of proteasome subunits. Cancer. 2008;112:659–70.CrossRefPubMed
38.
Kraus M, Ruckrich T, Reich M, Gogel J, Beck A, Kammer W, et al. Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells. Leukemia. 2007;21:84–92.CrossRefPubMed
39.
Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C. Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia. 2000;14:399–402.CrossRefPubMed
40.
Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001;98:2301–7.CrossRefPubMed
41.
Magrangeas F, Moreau P, Campion L, Avet-Loiseau H, Guérin C, Gouraud W, et al. Low level of NF-Kb activity is associated with higher response rate to bortezomib-based induction therapy in patients with newly diagnosed multiple myeloma. ASH Annu Meet Abstr. 2013;122:3106.
Metadata
Title
Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy
Authors
Denise Niewerth
Gertjan J. L. Kaspers
Gerrit Jansen
Johan van Meerloo
Sonja Zweegman
Gaye Jenkins
James A. Whitlock
Stephen P. Hunger
Xiaomin Lu
Todd A. Alonzo
Peter M. van de Ven
Terzah M. Horton
Jacqueline Cloos
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0312-z

Other articles of this Issue 1/2016

Journal of Hematology & Oncology 1/2016 Go to the issue

Review

How do we choose the best donor for T-cell-replete, HLA-haploidentical transplantation?

Research

Phase II trial of utidelone as monotherapy or in combination with capecitabine in heavily pretreated metastatic breast cancer patients

Research

Short telomere length and its correlation with gene mutations in myelodysplastic syndrome

Research

The expression profile and clinic significance of the SIX family in non-small cell lung cancer

Research

Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia

Research

Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits