High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib

Abstract

High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomibMultiple myeloma (MM) is a hematologic tumor characterized by accumulation of monoclonal plasma cells (PCs) in the bone marrow (BM) producing antigen-specific immunoglobulins. The transcription factor X box binding protein 1 (XBP1), the interferon regulatory factor 4 (IRF4) and the transcriptional repressor B lymphocite-induced maturation protein 1 (BLIMP1) are essential to drive physiological plasmacytic differentiation.1,2 XBP1 is particularly required for the last stages of B-cell differentiation into PC, and, consistently, XBP1-deficient mice display normal Blymphocite development up to germinal center, but are unable to produce PCs.2 High mRNA levels of IRF4, BLIMP1 and XBP1 have been detected in malignant PC and are negative prognostic factors in patients treated with standard chemotherapy or thalidomide.3,4 Lenalidomide seems to overcome the negative prognostic impact of IRF4 overexpression, due to its rapid downregulation following treatment. Bortezomib induces better responses in patients with high levels of XBP1. 5,6We assessed the prognostic role of gene-driven plasmacytic differentiation in a large cohort of patients treated with bortezomib. RNA expression of three genes involved in PCs differentiation was investigated in purified PCs (CD138 + BM fraction) of well-characterized patients with newly diagnosed MM. One hundred and fifty-one patients enrolled in two multicenter clinical trials (the PAD-MEL100-LP-L and the VMP-VMPT) were assessed.7,8 PCs were purified using anti-CD138-coated magnetic MicroBeads and AutoMACS Pro Separator (Miltenyi Biotech GmbH, Germany) following manufacturer specifications. Gene expression was investigated on isolated PCs with more than 90% of purity assessed by flow cytometry. RNA was extracted using the DNA/RNA Purification Kit (Norgen, Thorold, Canada). Complementary DNA was produced using High capacity cDNA RT Kit (Applied Biosytem, Foster Ciy, CA, USA). Quantitative PCR to measure RNA expression of XBP1, IRF4 and BLIMP1 was performed with the Abi Prism 7900HT (Applied Biosystems, Carlsbad, CA, USA) using a relative quantification based on ΔΔCt approach and GUSB (b-glucuronidase) as housekeeping gene. All RNA determinations were performed using the following assays: © F e r r a t a S t o r t i F o u n d a t i o ning to gene expression using the median value as cut off.Response to therapy and clinical outcome were assessed following IMWG criteria. 9 The progression-free survival (PFS) and overall survival (OS) were estimated by the Cox proportional hazard model, comparing the risk factors by the Wald test; best response was treated as a time-dependent variable. Patients' characteristics were compared by the Fisher's exact test for the categorical variables and the Mann-Whitney test for the continuous ones. All reported P-values were two-sided, at the conventional 5% significance level. Data were analyzed as of January 2013 by SPSS 21.0.0 and R 3.0.1 package surviva...

Novel therapeutic strategies for multiple myeloma

“…For example, lower XBP1s/u ratio is correlated with better response to thalidomide treatment [50]; in contrast, bortezomib is more effective in patients with high XBP1 levels [51, 52]. More recently, Leung-Hagesteijn et al have reported that XBP1s is required for bortezomib-induced cytotoxicity in MM; and conversely, that the XBP1s-negative MM subset with arrested secretory maturation becomes resistant to bortezomib [53].…”

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

“…In these cells, XBP1 defi ciency resulted in the acquisition of phenotypes that are disadvantageous for leukemia cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1; this occurred most likely through the attenuation of the adaptive capacity of the secretory pathway and the subsequent impact on both intrinsic cellular metabolism and the tumor microenvironement. Similarly, high levels of XBP1s may also predict a better outcome for the treatment of multiple myeloma patients with bortezomib, most likely through an established addiction to the signals mediated by this transcription factor ( 94,95 ).…”

Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma

“…Ling et al and Gambella et al have reported that XBP1, a downstream of activated IRE1 involved in UPR, is associated with the clinical outcome of MM patients who received BTZ-containing therapy. In their reports, a low expression of the XBP1 gene is observed in primary MM samples from patients who respond poorly to bortezomib and dexamethasone (BD) treatment [27], and a high expression of XBP1 is defined as a good prognosis marker of survival among patients receiving BTZ-containing regimen [28]. In our study, we investigated 57 patients with RR MM treated with BD in Nagoya City University Hospital (Fig.…”