Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy
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Dominik Dytfeld1,9,*, Magdalena Luczak2,11,*, Tomasz Wrobel3,9, Lidia Usnarska-Zubkiewicz3, Katarzyna Brzezniakiewicz3,9, Krzysztof Jamroziak5,9, Krzysztof Giannopoulos6,9, Anna Przybylowicz-Chalecka1, Blazej Ratajczak1, Joanna Czerwinska-Rybak1, Adam Nowicki1,9, Monika Joks1,9, Elzbieta Czechowska7,9, Magdalena Zawartko8, Tomasz Szczepaniak1,9, Norbert Grzasko6,9, Marta Morawska6,9, Maciej Bochenek1, Tadeusz Kubicki1, Michalina Morawska4,9, Katarzyna Tusznio5, Andrzej Jakubowiak10, Mieczysław Komarnicki1
1Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland
2nstitute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
3Department of Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland
4Department of Hematology, Hospital in Gorzow Wlkp, Gorzow Wlkp, Poland
5Institute of Hematology and Transfusiology, Warsaw, Poland
6Experimental Hematooncology Department, Medical University of Lublin and Hematology Department, St John's Cancer Center in Lublin, Lublin, Poland
7Department of Internal Medicine and Hematology, Stanisław Staszic Specialist Hospital, Piła, Poland
8Department of Hematology, 109 Military Hospital, Szczecin, Poland
9Researchers of Polish Myeloma Consortium
10University of Chicago, Chicago, IL, USA
11Institute of Chemical Technology and Engineering, Poznan University of Technology, Poznan, Poland
*These authors contributed equally to this work
Dominik Dytfeld, email: email@example.com
Keywords: multiple myeloma, bortezomib, label-free proteomics, iTRAQ, thioredoxin
Received: June 08, 2016 Accepted: July 20, 2016 Published: August 04, 2016
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.
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