DEPTOR maintains plasma cell differentiation and favorably affects prognosis in multiple myeloma

Abstract

BackgroundThe B cell maturation process involves multiple steps, which are controlled by relevant pathways and transcription factors. The understanding of the final stages of plasma cell (PC) differentiation could provide new insights for therapeutic strategies in multiple myeloma (MM). Here, we explore the role of DEPTOR, an mTOR inhibitor, in the terminal differentiation of myeloma cells, and its potential impact on patient survival.MethodsThe expression level of DEPTOR in MM cell lines and B cell populations was measured by real-time RT-PCR, and/or Western blot analysis. DEPTOR protein level in MM patients was quantified by capillary electrophoresis immunoassay. RNA interference was used to downregulate DEPTOR in MM cell lines.ResultsDEPTOR knockdown in H929 and MM1S cell lines induced dedifferentiation of myeloma cells, as demonstrated by the upregulation of PAX5 and BCL6, the downregulation of IRF4, and a clear reduction in cell size and endoplasmic reticulum mass. This effect seemed to be independent of mTOR signaling, since mTOR substrates were not affected by DEPTOR knockdown. Additionally, the potential for DEPTOR to be deregulated in MM by particular miRNAs was investigated. The ectopic expression of miR-135b and miR-642a in myeloma cell lines substantially diminished DEPTOR protein levels, and caused dedifferentiation of myeloma cells. Interestingly, the level of expression of DEPTOR protein in myeloma patients was highly variable, the highest levels being associated with longer progression-free survival.ConclusionsOur results demonstrate for the first time that DEPTOR expression is required to maintain myeloma cell differentiation and that high level of its expression are associated with better outcome.Primary samples used in this study correspond to patients entered into GEM2010 trial (registered at www.clinicaltrials.gov as #NCT01237249, 4 November 2010).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0461-8) contains supplementary material, which is available to authorized users.

A compendium of long non-coding RNAs transcriptional fingerprint in multiple myeloma

“…ILF2 overexpression deregulates homologous recombination (HR) by stabilizing the mRNA splicing of critical HR effectors, which enables genomic instability, promotes adaptive mechanisms to genotoxic stress, and enhances cell survival, thereby promoting drug resistance and disease progression 37 . As regards KB-1471A8.1 , it maps at 8q24 antisense to the 5′ region of DEPTOR , a crucial gene in the maintenance of the terminal differentiation of MM cells 38 . Since the overexpression of DEPTOR in MM has been associated with MAF translocations and the expression of CCND1 and CCND3 genes 39 , the downregulation of KB-1471A8.1 in HD-MM further suggest a cis-regulatory connection with DEPTOR .…”

FAM46C controls antibody production by the polyadenylation of immunoglobulin mRNAs and inhibits cell migration in multiple myeloma

“…Gene expression profiling of lymphomas from the Emu‐myc transgenic mice identified FAM46C among the genes included in the B lymphocyte developmental signature using the GSEA platform (MSigDB M1487 geneset, Table ). These results suggested that FAM46C might be involved in PC differentiation, so we first quantified FAM46C mRNA levels by qRT‐PCR in four BC populations, immature, naïve, memory B cells and PCs isolated from BM samples obtained from healthy donors . FAM46C expression was significantly higher in PCs than in the earlier stages of differentiation (Figure A, left panel) and was similar in PCs and in HMCLs (Figure A, right panel).…”

Identification of a microRNA signature associated with survivability in cervical squamous cell carcinoma

“…It is found that hsa-mir-642a is over expressed in the pediatric embryonal central nervous system neoplasm that is regarded as a prognostic parameter of patients [ 31 ]. In addition, the abnormal expression of hsa-mir-642a in myeloma cell lines significantly decreased protein levels of DEP domain containing MTOR interacting, which caused dedifferentiation of myeloma cells [ 32 ]. It is noteworthy that hsa-mir-642a is associated with cervical cancer prognosis [ 33 ].…”