Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2016 Aug 30;7(35):56726-56736.
doi: 10.18632/oncotarget.11059.

Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy

Dominik Dytfeld  1   2 , Magdalena Luczak  3   4 , Tomasz Wrobel  5   2 , Lidia Usnarska-Zubkiewicz  5 , Katarzyna Brzezniakiewicz  5   2 , Krzysztof Jamroziak  6   2 , Krzysztof Giannopoulos  7   2 , Anna Przybylowicz-Chalecka  1 , Blazej Ratajczak  1 , Joanna Czerwinska-Rybak  1 , Adam Nowicki  1   2 , Monika Joks  1   2 , Elzbieta Czechowska  8   2 , Magdalena Zawartko  9 , Tomasz Szczepaniak  1   2 , Norbert Grzasko  7   2 , Marta Morawska  7   2 , Maciej Bochenek  1 , Tadeusz Kubicki  1 , Michalina Morawska  10   2 , Katarzyna Tusznio  6 , Andrzej Jakubowiak  11 , MieczysÅ Aw Komarnicki  1
Affiliations
Comparative Study

Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy

Dominik Dytfeld et al. Oncotarget. .

Abstract

Identifying biomarkers of the resistance in multiple myeloma (MM) is a key research challenge. We aimed to identify proteins that differentiate plasma cells in patients with refractory/relapsed MM (RRMM) who achieved at least very good partial response (VGPR) and in those with reduced response to PAD chemotherapy (bortezomib, doxorubicin and dexamethasone). Comparative proteomic analysis was conducted on pretreatment plasma cells from 77 proteasome inhibitor naïve patients treated subsequently with PAD due to RRMM. To increase data confidence we used two independent proteomic platforms: isobaric Tags for Relative and Absolute Quantitation (iTRAQ) and label free (LF). Proteins were considered as differentially expressed when their accumulation between groups differed by at least 50% in iTRAQ and LF. The proteomic signature revealed 118 proteins (35 up-regulated and 83 down-regulated in ≥ VGPR group). Proteins were classified into four classes: (1) involved in proteasome function; (2) involved in the response to oxidative stress; (3) related to defense response; and (4) regulating the apoptotic process. We confirmed the differential expression of proteasome activator complex subunit 1 (PSME1) by enzyme-linked immunosorbent assay. Increased expression of proteasomes and proteins involved in protection from oxidative stress (eg., TXN, TXNDC5) plays a major role in bortezomib resistance.

Keywords: bortezomib; iTRAQ; label-free proteomics; multiple myeloma; thioredoxin.

PubMed Disclaimer

Conflict of interest statement

No conflicts of interest.

Figures

Figure 1
Figure 1. Representative correlation plots comparing the LFQ intensities and iTRAQ reporter ion intensities of two biological replications for the CR/VGPR (A) and < VGPR (B) groups
The Pearson correlation coefficient is provided for each plot.
Figure 2
Figure 2. A Venn diagram comparing the results from the LF and iTRAQ (ESI and MALDI) techniques
The numbers indicate differential proteins identified with two peptides using each approach.
Figure 3
Figure 3. Serum concentrations of PSME1 in patients who achieved CR/VGPR (n = 16) to the PAD regimen vs. patients with lower response (<VGPR, n = 16)
The controls were healthy subjects (n = 6). The results are presented as the mean ± standard error of the mean (SEM).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR, Dispenzieri A, Fonseca R, Sher T, Kyle RA, Lin Y, Russell SJ, Kumar S, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013;88:360–76. - PubMed
    1. Durie BGM, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73. - PubMed
    1. Dytfeld D, Rosebeck S, Kandarpa M, Mayampurath A, Mellacheruvu D, Alonge MM, Ngoka L, Jasielec J, Richardson PG, Volchenboum S, Nesvizhskii AI, Sreekumar A, Jakubowiak AJ. Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib-based treatment regimens. Br J Haematol. 2015;170:66–79. - PubMed
    1. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72. - PubMed
    1. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen J V, Mann M. Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res. 2011;10:1794–805. - PubMed

Publication types

MeSH terms