title: Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy.
abstract: Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS<6 months (n=33) and a second group with PFS⩾6 months (n=23). Of the 15 genes analyzed, the expression of activating transcription factor 3 (ATF3) and ATF4 was significantly lower in patients with shorter PFS (P=0.0157 and P=0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa, which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Narita
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ri
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Masaki
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Mori
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kusumoto
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Iida
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D017209:Apoptosis; D015415:Biomarkers; D000069286:Bortezomib / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; D015415:Biomarkers; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051701:Activating Transcription Factor 4; D000069286:Bortezomib; D003907:Dexamethasone