title: Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy.
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.
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Dominik
authors.initials: D
authors.lastname: Dytfeld
authors.affiliation: nstitute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.|Institute of Chemical Technology and Engineering, Poznan University of Technology, Poznan, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Luczak
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wrobel
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Usnarska-Zubkiewicz
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Brzezniakiewicz
authors.affiliation: Institute of Hematology and Transfusiology, Warsaw, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jamroziak
authors.affiliation: Experimental Hematooncology Department, Medical University of Lublin and Hematology Department, St John's Cancer Center in Lublin, Lublin, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Giannopoulos
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Przybylowicz-Chalecka
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Blazej
authors.initials: B
authors.lastname: Ratajczak
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Czerwinska-Rybak
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Adam
authors.initials: A
authors.lastname: Nowicki
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Monika
authors.initials: M
authors.lastname: Joks
authors.affiliation: Department of Internal Medicine and Hematology, StanisÅaw Staszic Specialist Hospital, PiÅa, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Czechowska
authors.affiliation: Department of Hematology, 109 Military Hospital, Szczecin, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zawartko
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Szczepaniak
authors.affiliation: Experimental Hematooncology Department, Medical University of Lublin and Hematology Department, St John's Cancer Center in Lublin, Lublin, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Norbert
authors.initials: N
authors.lastname: Grzasko
authors.affiliation: Experimental Hematooncology Department, Medical University of Lublin and Hematology Department, St John's Cancer Center in Lublin, Lublin, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Marta
authors.initials: M
authors.lastname: Morawska
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Bochenek
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Kubicki
authors.affiliation: Department of Hematology, Hospital in Gorzow Wlkp, Gorzow Wlkp, Poland.|Researchers of Polish Myeloma Consortium.
authors.forename: Michalina
authors.initials: M
authors.lastname: Morawska
authors.affiliation: Institute of Hematology and Transfusiology, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Tusznio
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Jakubowiak
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: MieczysÅ Aw
authors.initials: MA
authors.lastname: Komarnicki
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000069286:Bortezomib / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D018384:Oxidative Stress; D040901:Proteomics; D053719:Tandem Mass Spectrometry; D013879:Thioredoxins / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D013879:Thioredoxins; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin
keywords: bortezomib; iTRAQ; label-free proteomics; multiple myeloma; thioredoxin