scholarly journals Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3849-3855 ◽  
Author(s):  
Frederic Luciano ◽  
Maryla Krajewska ◽  
Paulina Ortiz-Rubio ◽  
Stan Krajewski ◽  
Dayong Zhai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Interference ◽  
Plasma Cells ◽  
Orphan Nuclear Receptor ◽  
Myeloma Cells ◽  
Antiapoptotic Protein ◽  
Induced Apoptosis ◽  
Selective Reactivity ◽  
Rpmi 8226 ◽  
Dependent Mechanism

Abstract Defects in apoptosis mechanisms play important roles in malignancy and autoimmunity. Orphan nuclear receptor Nur77/TR3 has been demonstrated to bind antiapoptotic protein Bcl-2 and convert it from a cytoprotective to a cytodestructive protein, representing a phenotypic conversion mechanism. Of the 6 antiapoptotic human Bcl-2 family members, we found that Nur77/TR3 binds strongest to Bcl-B, showing selective reactivity with Bcl-B, Bcl-2, and Bfl-1 but not Bcl-XL, Mcl-1, or Bcl-W. Nur77 converts the phenotype of Bcl-B from antiapoptotic to proapoptotic. Bcl-B is prominently expressed in plasma cells and multiple myeloma. Endogenous Bcl-B associates with endogenous Nur77 in RPMI 8226 myeloma cells, where RNA interference experiments demonstrated dependence on Bcl-B for Nur77-induced apoptosis. Furthermore, a Nur77-mimicking peptide killed RPMI 8226 myeloma cells through a Bcl-B–dependent mechanism. Because Bcl-B is abundantly expressed in plasma cells and some myelomas, these findings raise the possibility of exploiting the Nur77/Bcl-B mechanism for apoptosis for eradication of autoimmune plasma cells or myeloma.

Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3354-3362 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Marloes M. J. Kamphuis ◽  
Berris van Kessel ◽  
Henk M. Lokhorst ◽  
Andries C. Bloem
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Mevalonate Pathway ◽  
Cytochrome C Release ◽  
Hmg Coa Reductase ◽  
Myeloma Cells ◽  
Protein Levels ◽  
Geranylgeranyl Transferase ◽  
Induced Apoptosis ◽  
Coa Reductase

AbstractHMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.

Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 610-618 ◽  
Author(s):  
Inge Tinhofer ◽  
Ingrid Marschitz ◽  
Traudl Henn ◽  
Alexander Egle ◽  
Richard Greil
Keyword(s):  
Multiple Myeloma ◽  
Cell Survival ◽  
Cell Lines ◽  
Plasma Cells ◽  
Constitutive Expression ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Cytotoxic Treatment ◽  
Interleukin 15 ◽  
Induced Apoptosis

Interleukin-15 (IL-15) induces proliferation and promotes cell survival of human T and B lymphocytes, natural killer cells, and neutrophils. Here we report the constitutive expression of a functional IL-15 receptor (IL-15R) in 6 of 6 myeloma cell lines and in CD38high/CD45low plasma cells belonging to 14 of 14 patients with multiple myeloma. Furthermore, we detected IL-15 transcripts in all 6 myeloma cell lines, and IL-15 protein in 4/6 cell lines and also in the primary plasma cells of 8/14 multiple myeloma patients. Our observations confirm the existence of an autocrine IL-15 loop and point to the potential paracrine stimulation of myeloma cells by IL-15 released from the cellular microenvironment. Blocking autocrine IL-15 in cell lines increased the rate of spontaneous apoptosis, and the degree of this effect was comparable to the pro-apoptotic effect of depleting autocrine IL-6 by antibody targeting. IL-15 was also capable of substituting for autocrine IL-6 in order to promote cell survival and vice versa. In short-term cultures of primary myeloma cells, the addition of IL-15 reduced the percentage of tumor cells spontaneously undergoing apoptosis. Furthermore, IL-15 lowered the responsiveness to Fas-induced apoptosis and to cytotoxic treatment with vincristine and doxorubicin but not with dexamethasone. These data add IL-15 to the list of important factors promoting survival of multiple myeloma cells and demonstrate that it can be produced and be functionally active in an autocrine manner.

scholarly journals A Role for Syntenin-1 in Multiple Myeloma Cell Survival

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1008-1008
Author(s):  
Tyler Moser-Katz ◽  
Catherine M. Gavile ◽  
Benjamin G Barwick ◽  
Sagar Lonial ◽  
Lawrence H. Boise
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Death ◽  
Cell Survival ◽  
Cell Lines ◽  
Plasma Cells ◽  
Surface Expression ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Rpmi 8226

Abstract Multiple myeloma is the second most common hematological malignancy in the U.S. with an estimated 30,700 new diagnoses in 2018. It is a clonal disease of plasma cells that, despite recent therapeutic advances, remains incurable. Myeloma cells retain numerous characteristics of normal plasma cells including reliance on survival signals in the bone marrow for long term viability. However, malignant transformation of plasma cells imparts the ability to proliferate, causing harmful bone lesions in patients, and in advanced stages independence of the bone-marrow microenvironment. Therefore, we are investigating the molecular mechanisms of myeloma cell survival that allow them to become extramedullary. We identified syntenin-1 (SDCBP) as a protein involved in myeloma cell survival and a potential therapeutic target. Syntenin-1 is an adapter protein that has been shown to regulate surface expression of several transmembrane proteins by binding with membrane phospholipids and mediating vesicular trafficking of proteins throughout the cell. Syntenin-1 regulates the surface expression of CD138, a plasma/myeloma cell marker. Syntenin-1 has been shown to regulate apoptosis in numerous cancer cell lines including breast cancer, glioma, and pancreatic cancer but its role in multiple myeloma survival has not been studied. To determine if syntenin-1 expression has an effect on myeloma cell survival, we utilized the CoMMpass dataset (IA12), a longitudinal study of myeloma patients that includes transcriptomic analysis throughout treatment. We found that patients with the highest expression of syntenin-1 mRNA (top quartile) had significantly worse overall survival, progression-free survival, and a shorter response duration than those in the bottom quartile of expression. To determine if syntenin-1 has a role in myeloma cell survival, we used short hairpin RNA to knock down syntenin-1 (shsyn) in RPMI 8226 and MM1.s myeloma cell lines. We then determined the amount of cell death using Annexin-V staining flow cytometry four days following lentiviral infection. We found increased cell death in syntenin-1-silenced cells compared to our empty vector control in both RPMI 8226 (control=42.17%, shsyn=71.53%, p=0.04) and MM1.s cell lines (control=8.57%, shsyn=29.9%, p=0.04) suggesting that syntenin-1 is important for myeloma cell survival. Syntenin-1 contains two PDZ domains that allow it to bind to receptor proteins via their corresponding PDZ-binding motifs. We therefore wanted to look at correlation of syntenin-1 expression with CD138 and CD86, two PDZ-binding domain containing proteins expressed on the surface of myeloma cells. Using the CoMMpass dataset, we found patients with high expression of syntenin-1 had a median expression of CD86 that was twice as high as the total population (P<0.0001) while syntenin-1-low patients expressed CD86 at levels that were half as much as the population (P<0.0001). In contrast, there was no clear relationship between syntenin-1 and CD138 mRNA expression. Indeed if one takes into account all patients, there is a positive correlation between CD86 and syntenin-1 expression (r=0.228, P<0.0001) while there is a negative correlation between CD138 and syntenin-1 (r=-0.1923, P<0.0001). The correlation with CD86 but not CD138 suggests a previously undescribed role for syntenin-1 in myeloma cells. Our lab has previously shown that expression of CD86 is necessary for myeloma cell survival, and signals via its cytoplasmic domain to confer drug resistance. Silencing syntenin-1 results in a decrease in CD86 surface expression. However, there is no change in CD86 transcript or total cellular CD86 protein levels in our shsyn treated cells. Moreover, knockdown of CD86 resulted in increased protein expression and transcript levels of syntenin-1. Taken together, these data suggest that syntenin-1 may regulate CD86 expression on the cell surface. Our data supports a novel role for syntenin-1 in myeloma cell viability and as a potential regulator of CD86 surface expression. The role of syntenin-1 has not previously been explored in multiple myeloma and determining its molecular function is warranted as it may be an attractive target for therapeutic treatment of the disease. Disclosures Lonial: Amgen: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy.

scholarly journals The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sook-Kyoung Heo ◽  
Eui-Kyu Noh ◽  
Jeong Yi Kim ◽  
Ho-Min Yu ◽  
Jun Young Sung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tyrosine Kinase ◽  
Cancer Progression ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Treatment Options ◽  
Annexin V ◽  
Cancer Drug ◽  
Myeloma Cells ◽  
Rpmi 8226

AbstractMultiple myeloma (MM) is a hematological cancer resulting from accumulated abnormal plasma cells. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and the platelet-derived growth factor receptor. Generally, the mechanism of inhibition of non-receptor tyrosine kinase c-Abl has played an essential role in the inhibition of cancer progression. However, little is known regarding the effects of the c-Abl inhibitor, radotinib on MM cells. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Interestingly, radotinib caused apoptosis in MM cells including RPMI-8226, MM.1S, and IM-9 cells, even in the absence of c-kit expression in 2 of these lines. Radotinib treatment significantly increased the number Annexin V-positive cells and decreased the mitochondrial membrane potential in MM cells. Additionally, we observed that cytochrome C was localized in the cytosol of radotinib-treated MM cells. Moreover, radotinib decreased the expression of Bcl-2 and Bcl-xL, and increased the expression of Bax and Bak in MM cells. Furthermore, radotinib promoted caspase pathway activation by inducing the expression and activity of caspase-3, -7, and -9. Expression of cleaved PARP-1 was also increased by radotinib treatment in various MM cells. In addition, radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells, and killed ex vivo myeloma cells from patients. In conclusion, radotinib may play an important role as a candidate agent or chemosensitizer for the treatment of MM.

Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3379-3386 ◽  
Author(s):  
Dharminder Chauhan ◽  
Guilan Li ◽  
Teru Hideshima ◽  
Klaus Podar ◽  
Constantine Mitsiades ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Caspase 3 ◽  
Mitochondrial Protein ◽  
Caspase 9 ◽  
Apoptotic Response ◽  
Myeloma Cells ◽  
Dexamethasone Resistance ◽  
Induced Apoptosis ◽  
Rpmi 8226

AbstractSmac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.

MEK1 Blockade Sensitizes Multiple Myeloma Tumor Cells to Arsenic Trioxide (ATO)-Induced Apoptosis: A Functional and Molecular Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1372-1372
Author(s):  
Paolo Lunghi ◽  
Nicola Giuliani ◽  
Laura Mazzera ◽  
Francesca Morandi ◽  
Vittorio Rizzoli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Index ◽  
Combined Treatment ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Myeloma Cells ◽  
Induction Of Apoptosis ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Rpmi 8226

Abstract Preliminary data from clinical studies indicate that ATO has clinical activity as a single agent in human multiple myeloma (MM), and combination therapies are being investigated. We recently reported that PD184352 (PD) ( Pfizer), a highly selective inhibitor of MEK1, strikingly enhances ATO-mediated apoptosis in NB4, K562 cell lines and in Acute Myelogenous Leukemia via multiple intrinsic apoptotic pathways activation. The aim of this study was to investigate whether the combined treatment with PD and ATO has cytotoxic effects on MM cells. We first analyzed the pharmacologic interactions between PD (2 μM) and ATO (1–2 μM) using a fixed-ratio experimental design on 7 human myeloma cell lines (HMCL) with varying p53 status (RPMI 8226, U266, XG-1, XG-6, JJN3, HS-SULTAN, NCI-H929) and found that the combined treatment resulted in the synergistic (Combination Index &lt;1.0) induction of apoptosis in NCI-H929, XG-1, XG-6, RPMI 8226, SULTAN and JJN3 HMCL. Conversely, the combination of PD plus ATO had a slight antagonistic effect on apoptosis induction in U266 HMCL (Combination Index &gt;1). Moreover, PD plus ATO-induced cytotoxicity on HMCL was maintained also in presence of IL-6 (20 ng/ml) or in a co-culture system with bone marrow stromal cells. Similarly to HMCL we found that the treatment with PD significantly enhanced the apoptosis of fresh purified MM cells induced by ATO (P&lt; .01) in 8 out of 11 patients of MM analyzed. Conversely, PD treatment partially attenuated (n=2) or did not affect (n=1) the ATO cytotoxicity in normal bone marrow B cells. To investigate the molecular mechanisms by which PD plus ATO induced MM cell apoptosis first we compared the effect on caspase activation in myeloma cells expressing wild type (wt) p53 or mutated p53. Using caspase blocking peptides, specific siRNA against caspase-8 or caspase-9 and Western immunoblotting we demonstrated the involvement of primarily caspase-8 and -3 in PD plus ATO-induced apoptosis in myeloma cells with mutated p53 and primarily caspase-9 and -3 in dual treated cells expressing wt p53. In addition, PD plus ATO induced a p53-dependent up regulation of Puma, Bax and Bak in HMCL with wt p53, and p53-specific siRNA significantly (P&lt; .01) reduced the induction of apoptosis in dual treated cells. The caspase-8-mediated proteolytic activation of BID, a key protein involved in the cross-talk between the intrinsic and extrinsic apoptotic pathways, closely correlated with the caspase-9 activation and loss of mitochondrial membrane potential observed in dual treated HMCL with mutated p53. Finally, in the responsive HMCL both with wt or mutated p53, the combined treatment increased the level of the pro-apoptotic Bim (PD-mediated) and decreased its neutralizing anti-apoptotic protein Mcl-1 (ATO-mediated) causing an imbalance between these proteins that positively influenced the pro-apoptotic efficacy of the combination. In conclusion, our data indicate that the disruption of MEK pathway potentiates the apoptotic effect of ATO in MM cells through the activation of both extrinsic and intrinsic (caspase-8-BID-mediated) pathways in HMCL with mutated p53 or through the primarily activation of intrinsic pathway in HMCL with wt p53, with the positive contribution of Bim pathway. These findings suggest that a strategy combining ATO with disruption of MEK pathway could represent an effective therapeutic strategy for the treatment of MM.

Ritonavir Sensitizes Multiple Myeloma Cells to Bortezomib-Induced Apoptosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5194-5194
Author(s):  
Robert Shibata ◽  
Florian Bassermann ◽  
Pranil Chandra ◽  
Henrike Resemann ◽  
Amitabha Mazumder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cell Cancer ◽  
Growth Arrest ◽  
26S Proteasome ◽  
Cell Cycle Regulators ◽  
Myeloma Cells ◽  
Induced Apoptosis ◽  
Rpmi 8226

Abstract The ubiquitin-proteasome system plays a central role in the regulation of cell growth and cell proliferation by controlling the abundance of key cell cycle proteins. Increasing evidence indicates that unscheduled proteolysis of many cell cycle regulators contributes significantly to tumourigenesis and is indeed found in many types of human cancers, including colon and renal cell cancer, non hodgkin lymphomas, and multiple myelomas. Protein degradation pathways are also targets for cancer therapy, as shown by the successful introduction of bortezomib (B), an inhibitor of the 26S proteasome, for the therapy of multiple myeloma. Recently, protease inhibitors conventional in HIV therapy (e.g., ritonavir (R)) have been found to exert an antiproliferative effect on different tumor types, including multiple myeloma cells. More recently, ritonavir has been shown to induce endoplasmic reticulum stress and to sensitize sarcoma cells towards bortezomib induced apoptosis. In this study, we show that the combination of therapeutic concentrations of bortezomib and ritonavir acts synergistically on cultured multiple myeloma cell lines (U266, RPMI 8226, ARH-77 (2 variants-One is more resistant)). Cell proliferation was significantly reduced in an overadditive fashion as compared to individual treatments (proliferation as % of DMSO control after 48hrs: CRL-1621 (ARH-77): B: 40%, R: 50%, R&B: 7%, CCL-155 (RPMI 8226): B: 37%, R: 50%, B+R: 6%; n=3). Moreover, we found proteasome inhibition by bortezomib to be associated with low levels of expression of Skp2 and consequent stabilization of its target p27Kip1, a negative cell cycle regulator at the G1/S cell cycle transition. Accordingly, bortezomib induced cell cycle arrest at the G1/S transition followed by caspase dependent apoptosis. In contrast, only mild induction of apoptosis and no activation of Caspase 3 were observed in myeloma cells treated with ritonavir, although growth arrest was present. Interestingly, growth arrest in ritonavir-treated cells was associated with an accumulation in G2 phase. In a limited clinical study, we treated two patients with stage III relapsed and refractory myeloma with a combination of bortezomib at standard doses and ritonavir at 600 mg twice a day. Both patients had MR or greater lasting for more than 2 months. Only grade 2 GI toxicity was seen. Taken together, our findings suggest different mechanisms of action for bortezomib and ritonavir on myeloma cells and suggest that the combination of the two drugs may be a valid therapeutic strategy.

Betulinic Acid Enhances the Sensitivity of Multiple Myeloma Cells to Bortezomib by the Inactivation of the AKT/mTOR Pathway

2020 ◽  
Vol 18 (3) ◽  
pp. 241-246
Author(s):  
Yu Dan ◽  
Wan Sheng ◽  
Hu Lili
Keyword(s):  
Multiple Myeloma ◽  
Betulinic Acid ◽  
Myeloma Cell ◽  
Mtor Pathway ◽  
Prolonged Treatment ◽  
Myeloma Cells ◽  
Multiple Myeloma Cell ◽  
Increased Sensitivity ◽  
Colony Number ◽  
Rpmi 8226

This study aimed to investigate the mechanism of betulinic acid on multiple myeloma cell resistance to bortezomib. To this end, the bortezomib-resistant RPMI-8226-R cells were generated by prolonged treatment of RPMI-8226 cells with increasing concentrations of bortezomib. Based on the measurements of cell viability and colony number, RPMI-8226-R cells exhibited enhanced resistance to bortezomib than RPMI-8226 cells. Treatment with betulinic acid resulted in increased sensitivity of RPMI-8226-R to bortezomib. When RPMI-8226-R cells were co-treated with bortezomib and betulinic acid, there was an increase in apoptosis rate, cleaved caspase-3, cleaved caspase-9 expression and the decrease in p-AKT/AKT and p-mTOR/mTOR levels. These results suggest that betulinic acid enhances the sensitivity of RPMI-8226-R cells to bortezomib by inhibiting the activation of the AKT/mTOR pathway in bortezomib-resistant multiple myeloma cells.

scholarly journals Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Laurie Herviou ◽  
Sara Ovejero ◽  
Fanny Izard ◽  
Ouissem Karmous-Gadacha ◽  
Claire Gourzones ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Histone H4 ◽  
Myeloma Cells ◽  
Functional Studies ◽  
Replicative Stress ◽  
Poor Outcome ◽  
Subsequent Decrease ◽  
Lysine Methyltransferase

Abstract Background Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. Results Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. Conclusions Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.

Sign in / Sign up

Export Citation Format

Share Document