Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1

Silvia C W Ling, Edwin K K Lau, Ammira S. Akil, Angela Nikolic, Albert Catalano, Harry Iland, Noemi Horvath, P. Joy Ho, Simon Harrison, Shaun Fleming, Douglas E. Joshua, John D. Allen

Research output: Contribution to journalArticle

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Abstract

Background: Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to borte-zomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib. Design and Methods: Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested. Results: Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself. Conclusions: The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).

Original languageEnglish
Pages (from-to)64-72
Number of pages9
JournalHaematologica
Volume97
Issue number1
DOIs
Publication statusPublished - 1 Jan 2012
Externally publishedYes

Fingerprint

Unfolded Protein Response
Proteasome Inhibitors
Proteasome Endopeptidase Complex
Plasma Cells
Cell Line
Immunoglobulins
Immunoglobulin Subunits
Bortezomib
Tunicamycin
Antibody-Producing Cells
Ubiquitin
Multiple Myeloma
Pharmaceutical Preparations
Registries
Neoplasms
Transcription Factors
Therapeutics
Biomarkers
Clinical Trials

Keywords

  • Bortezomib
  • Myeloma
  • Unfolded protein response
  • XBP-1

ASJC Scopus subject areas

  • Hematology

Cite this

Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1. / Ling, Silvia C W; Lau, Edwin K K; Akil, Ammira S.; Nikolic, Angela; Catalano, Albert; Iland, Harry; Horvath, Noemi; Ho, P. Joy; Harrison, Simon; Fleming, Shaun; Joshua, Douglas E.; Allen, John D.

In: Haematologica, Vol. 97, No. 1, 01.01.2012, p. 64-72.

Research output: Contribution to journalArticle

Ling, SCW, Lau, EKK, Akil, AS, Nikolic, A, Catalano, A, Iland, H, Horvath, N, Ho, PJ, Harrison, S, Fleming, S, Joshua, DE & Allen, JD 2012, 'Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1', Haematologica, vol. 97, no. 1, pp. 64-72. https://doi.org/10.3324/haematol.2011.043331
Ling, Silvia C W ; Lau, Edwin K K ; Akil, Ammira S. ; Nikolic, Angela ; Catalano, Albert ; Iland, Harry ; Horvath, Noemi ; Ho, P. Joy ; Harrison, Simon ; Fleming, Shaun ; Joshua, Douglas E. ; Allen, John D. / Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1. In: Haematologica. 2012 ; Vol. 97, No. 1. pp. 64-72.
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abstract = "Background: Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to borte-zomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib. Design and Methods: Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested. Results: Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself. Conclusions: The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).",
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AU - Nikolic, Angela

AU - Catalano, Albert

AU - Iland, Harry

AU - Horvath, Noemi

AU - Ho, P. Joy

AU - Harrison, Simon

AU - Fleming, Shaun

AU - Joshua, Douglas E.

AU - Allen, John D.

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N2 - Background: Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to borte-zomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib. Design and Methods: Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested. Results: Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself. Conclusions: The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).

AB - Background: Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to borte-zomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib. Design and Methods: Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested. Results: Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself. Conclusions: The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).

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