Plasma cell maturity as a predictor of prognosis in multiple myeloma

Iriyama, Noriyoshi; Miura, Katsuhiro; Hatta, Yoshihiro; Uchino, Yuichi; Kurita, Daisuke; Takahashi, Hiroyuki; Sakagami, H; Sakagami, Masashi; Kobayashi, Yohnosuke; Nakagawa, Masaru; Ohtake, S; Iizuka, Yoshikazu; Takei, Masami

doi:10.1007/s12032-016-0803-3

Cited by 12 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation is consistent with the fact that the patients included in our study received a treatment regimen that contained lenalidomide, a thalidomide-like drug. On the other hand, we have shown that DEPTOR induces PC maturation, and it has been reported that the maturation of myeloma cells is associated with sensitivity to anti-myeloma agents [30, 34, 45–47], including lenalidomide [45]. In fact, plasma cell maturity seems to be an indicator of good prognosis in MM [47].…”

Section: Discussionmentioning

confidence: 83%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 83%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Interestingly, both γSI and Sirtinol had also a potent effect on the expression of the maturation antigen CD49e (Fig. 5 ) that is a differentiation agent for MM cells and is associated with a better prognosis of MM patients 46 . Notably, miR-34a transfection caused a rebound/protective effect in MM cells with a strong reduction of CD49e expression that was however completely counteracted by both γSI and Sirtinol treatment, with even a final potentiation of antigen expression.…”

Section: Discussionmentioning

confidence: 96%

Evidence of novel miR-34a-based therapeutic approaches for multiple myeloma treatment

Zarone

Misso

Grimaldi

et al. 2017

Sci Rep

View full text Add to dashboard Cite

MiR-34a acts as tumor suppressor microRNA (miRNA) in several cancers, including multiple myeloma (MM), by controlling the expression of target proteins involved in cell cycle, differentiation and apoptosis. Here, we have investigated the combination between miR-34a and γ-secretase inhibitor (γSI), Sirtinol or zoledronic acid (ZOL) in order to enhance the inhibitory action of this miRNA on its canonical targets such as Notch1 and SIRT1, and on Ras/MAPK-dependent pathways. Our data demonstrate that miR-34a synthetic mimics significantly enhance the anti-tumor activity of all the above-mentioned anti-cancer agents in RPMI 8226 MM cells. We found that γSI enhanced miR-34a-dependent anti-tumor effects by activating the extrinsic apoptotic pathway which could overcome the cytoprotective autophagic mechanism. Moreover, the combination between miR-34a and γSI increased the cell surface calreticulin (CRT) expression, that is well known for triggering anti-tumor immunological response. The combination between miR-34a and Sirtinol induced the activation of an intrinsic apoptotic pathway along with increased surface expression of CRT. Regarding ZOL, we found a powerful growth inhibition after enforced miR-34a expression, which was not likely attributable to neither apoptosis nor autophagy modulation. Based on our data, the combination of miR-34a with other anti-cancer agents appears a promising anti-MM strategy deserving further investigation.

show abstract

“…The close relationship between Cdc37 and Xbp1s led us to ask whether Cdc37 also functions in plasma cell differentiation and maturation. We found that knockdown of Cdc37 by shRNA resulted in decreased secretion of Ig light chain and repressed expression of plasma cell maturation markers, such as Xbp1s, CD38, and CD49e 27,28 in NCI-H929 cells (Fig. 4a) and KMS11 cells (Fig.…”

Section: Suppression Of Cdc37 Induces Immaturity Of Plasma Cellsmentioning

confidence: 91%

Cdc37 suppression induces plasma cell immaturation and bortezomib resistance in multiple myeloma via Xbp1s

et al. 2020

View full text Add to dashboard Cite

Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Although the use of bortezomib (BTZ) significantly improves MM therapy, intrinsic and acquired drug resistance to BTZ remains a major clinical problem. In this study, we find that Cdc37, a key co-chaperone of Hsp90, is downregulated in relapsed MM patients, especially after BTZ treatment, suggesting a link between Cdc37 and BTZ resistance. Suppression of Cdc37 or inhibition of Cdc37/ Hsp90 association induces plasma cell dedifferentiation, quiescence of MM cells, and BTZ resistance in MM. Furthermore, we discover that Cdc37 expression correlates positively with Xbp1s, a critical transcription factor for plasma cell differentiation in MM samples. Depletion/inhibition of Cdc37 downregulates Xbp1s, while overexpression of Xbp1s in MM cell lines partially rescues plasma immaturation and BTZ resistance. It is suggested that Xbp1s may act as a key downstream effector of Cdc37. Experiments with a mouse model also demonstrate that Cdc37 inhibition promotes plasma cell immaturation, confers BTZ resistance, and increases MM progression in vivo. Together, we identify a critical factor and a new signaling mechanism that regulate plasma cell immaturation and BTZ resistance in MM cells. Our findings may constitute a novel strategy that overcomes BTZ resistance in MM therapy.

show abstract

Plasma cell maturity as a predictor of prognosis in multiple myeloma

Cited by 12 publications

References 31 publications

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

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

Evidence of novel miR-34a-based therapeutic approaches for multiple myeloma treatment

Cdc37 suppression induces plasma cell immaturation and bortezomib resistance in multiple myeloma via Xbp1s

Contact Info

Product

Resources

About