Apoptosis In Multiple Myeloma Research Articles

Novel Midkine Inhibitor Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma.

Multiple myeloma (MM), the second most common hematological malignancy, is characterized by the accumulation of malignant plasma cells within the bone marrow. Despite various drug classes for MM treatment, it remains incurable, necessitating novel and efficacious agents. This study aims to explore the anti-cancer activity of a midkine inhibitor, iMDK (C21H13FN2O2S), in myeloma cell lines. This study assessed the antiproliferative activity using the MTT assay. Cell cycle and apoptosis were evaluated using flow cytometry. To further investigate the inhibitory mechanism, western blotting was used to detect cell cycle-related proteins, pro-apoptotic proteins, and anti-apoptotic proteins. iMDK inhibits MM cell proliferation in a dose- and time-dependent manner, inducing cell cycle arrest and apoptosis. The reduction in Cdc20 expression by iMDK treatment leads to G2/M phase cell cycle arrest. Furthermore, iMDK down-regulates anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1, and c-FLIP), thereby activating both intrinsic and extrinsic apoptosis pathways. iMDK could be a potential candidate for MM treatment.

Small Molecule Inhibition of MAGE-A3 Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma

Background: The Type I Melanoma Antigen Gene-A3 (MAGE-A3) is commonly expressed in multiple myeloma (MM), a cancer of plasma cells. MAGE-A3 binds to Kap1 to form ubiquitin (Ub) ligase complexes and is associated with inhibition of apoptosis, resistance to chemotherapy, and cell cycle dysregulation. The highly conserved MAGE Homology Domain (MHD) undergoes a conformation change from “closed” to “open” in order to complex with Kap1, activate Ub ligase activity, and bind substrates. RNA interference (RNAi) knockdown of MAGE-A3 in MM cells results in upregulation of the endogenous CDK4/6 inhibitor P21 Cip1 and pro-apoptotic BIM, resulting in cell cycle arrest and intrinsic apoptosis. Knockdown of MAGE-A3 also increased cell death in response to melphalan and panobinostat, but not to bortezomib or cis-platin. These findings lead to the hypothesis that small molecule inhibition (SMI) of MAGE-A3 Ub ligase activity will have therapeutic application in this disease. Methods: We used the Schrodinger suite to perform in silico screening of a custom designed library of compounds using the crystal structure of the MAGE-A3 MHD to identify potential binding molecules that stabilize the closed MHD conformation. Candidates were then screened on human myeloma cell lines (HMCL) by CellTiter-Glo assay to identify compounds that reduced cell viability. Isothermal titration calorimetry was used to identify candidate SMI that bound to the MHD. HMCL were co-incubated with SMI; cell cycling was assessed by BrdU assay and apoptosis by Annexin V staining. Protein expression of p21 Cip1, BIM, and MAGE-A3 was assessed by Western blot. Combinatorial indexes in co-incubation experiments with ergotamine and chemotherapy agents were calculated with the Chou-Talalay method using CompuSyn. Results: Structure-based and biochemical screening nominated ergotamine as a candidate MAGE-A3 SMI. Ergotamine bound to the MAGE-A3 MHD and induced cell cycle arrest and apoptosis in MAGE-A3-expressing human myeloma and lymphoma cell lines and increased expression of pro-apoptotic BIM and p21 Cip1, similar to results with RNAi knockdown. These effects were not observed in negative control MAGE-A3(-) lymphoma cells. Co-incubation of ergotamine with chemotherapy agents melphalan or panobinostat resulted in synergistic killing of MAGE-A3+ HMCL. Ergotamine did not synergize with bortezomib or cis-platin under these conditions. Conclusions: These results support the combined structural and biochemical methods as an efficient means of screening for candidate inhibitors for MAGE-A3. Ergotamine recapitulated the results of RNAi knockdown of MAGE-A3 in cells that express the target, supporting a tool compound for further pharmacologic development. MAGE-A3 SMI have the potential to be a novel class of MM therapy that may be effective alone or in combination with chemotherapy or immune oncology agents. MAGE inhibitors may have broader application in other target-expressing cancers, including lung, melanoma, breast, and ovarian cancers, which are among the most common causes of cancer death.

Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

LTe2 induces cell apoptosis in multiple myeloma by suppressing AKT phosphorylation at Thr308 and Ser473.

Multiple myeloma (MM) is a highly heterogeneous hematological malignancy originating from B lymphocytes, with a high recurrence rate primarily due to drug resistance. 2-((1H-indol-3-yl)methyl)-3-((3-((1H-indol-3-yl)methyl)-1H-indol-2-yl)methyl)-1H-indole (LTe2), a tetrameric indole oligomer, possesses a wide range of anticancer activities through various mechanisms. Here, we aim to explore the anti-tumor efficiency and potential downstream targets of LTe2 in MM. Its bioactivity was assessed by employing MTT assays, flow cytometry, and the 5TMM3VT mouse model. Additionally, transcriptomic RNA-seq analysis and molecular dynamics (MD) experiments were conducted to elucidate the mechanism underlying LTe2 induced MM cell apoptosis. The results demonstrated that LTe2 significantly inhibited MM cell proliferation both in vitro and in vivo, and revealed that LTe2 exerts its effect by inhibiting the phosphorylation of AKT at the Thr308 and Ser473 sites. In summary, our findings highlight the potential of LTe2 as a novel candidate drug for MM treatment and provided a solid foundation for future clinical trials involving LTe2.

P-364 Novel FKBP12 targeting PROTACs enhances BMP-induced apoptosis in multiple myeloma

P-364 Novel FKBP12 targeting PROTACs enhances BMP-induced apoptosis in multiple myeloma

HIV-1 integrase inhibitor raltegravir promotes DNA damage-induced apoptosis in multiple myeloma.

Raltegravir, the first integrase inhibitor approved for the treatment of HIV infection, has been implicated as a promising potential in cancer treatment. Therefore, the present study aimed to investigate the repurposing of raltegravir as an anticancer agent and its mechanism of action in multiple myeloma (MM). Human MM cell lines (RPMI-8226, NCI H929, and U266) and normal peripheral blood mononuclear cells (PBMCs) were cultured with different concentrations of raltegravir for 48 and 72 h. Cell viability and apoptosis were then measured by MTT and Annexin V/PI assays, respectively. Protein levels of cleaved PARP, Bcl-2, Beclin-1, and phosphorylation of histone H2AX were detected by Western blotting. In addition, the mRNA levels of V(D)J recombination and DNA repair genes were analyzed using qPCR. Raltegravir treatment for 72 h significantly decreased cell viability, increased apoptosis, and DNA damage in MM cells while having minimum toxicity on cell viability of normal PBMCs approximately from 200 nM (0.2 μM; p < .01 for U66 and p < .0001 for NCI H929 and RPMI 8226 cells). Furthermore, raltegravir treatment altered the mRNA levels of V(D)J recombination and DNA repair genes. We report for the first time that treatment with raltegravir is associated with decreased cell viability, apoptosis induction, DNA damage accumulation, and alteration of mRNA expression of genes involved in V(D)J recombination and DNA repair in MM cell lines, all of which show its potential for anti-myeloma effects. Hence, raltegravir may significantly impact the treatment of MM, and further studies are required to confirm its efficacy and mechanism of action in more detail in patient-derived myeloma cells and in-vivo models.

Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma.

Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein-protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.

Recombinant human p53 adenovirus injection combined with Bortezomib inhibits proliferation and promotes apoptosis in multiple myeloma

BackgroundMultiple myeloma (MM) is a B-cell malignancy characterized by abnormal proliferation of clonal plasma cells in the bone marrow, the incidence of which has further increased in recent years. In multiple myeloma, wild-type functional p53 is often inactivated or dysregulated. Therefore, this study aimed to investigate the role of p53 knockdown or overexpression in multiple myeloma and the therapeutic effect of recombinant adenovirus-p53 (rAd-p53) in combination with Bortezomib. MethodsSiRNA p53 and rAd-p53 were used to knock down and overexpress p53. RT-qPCR was used to detect gene expression, and western blotting (WB) was used to detect protein expression levels. We also constructed wild-type multiple myeloma cell line-MM1S cell xenograft tumor models and explored the effects of siRNA-p53, rAd-p53, and Bortezomib on multiple myeloma in vivo and in vitro. H&E staining and KI67 immunohistochemical staining were used to assess the anti-myeloma effects of recombinant adenovirus and Bortezomib in vivo. ResultsThe designed siRNA p53 effectively led to the knockdown of the p53 gene, while rAd-p53 could significantly achieve p53 overexpression. p53 gene inhibited MM1S cell proliferation and promoted apoptosis of wild-type multiple myeloma cell line MM1S. P53 gene inhibited tumor proliferation in vitro by promoting p21 expression and reducing cell cycle protein B1 expression of MM1S. P53 gene overexpression could inhibit tumor growth in vivo. Injection of rAd-p53 in tumor models inhibited tumor development through p21- and cyclin B1-mediated cell proliferation and apoptosis regulation. ConclusionsWe found that overexpression of p53 inhibits MM tumor cell survival and proliferation in vivo and in vitro. Furthermore, the combination of rAd-p53 and Bortezomib significantly improved the efficacy, which provides a new possibility for more effective treatment of MM.

Exosomal circ-CACNG2 promotes cardiomyocyte apoptosis in multiple myeloma via modulating miR-197-3p/caspase3 axis

Multiple myeloma (MM) secreted exosomes are essential in MM-related complications such as osteolytic bone lesions and renal failure, but their role and underlying mechanism in cardiac complications has not yet been clarified. Here, we investigated the effects of U266 (a MM cell line) exosomes (U266-exo) on regulating the viability, cell cycle, oxidative stress and apoptosis of H9C2 cells and the role of circ-CACNG2 in these effects. We found that U266-exo coculture significantly inhibited viability and promoted apoptosis of H9C2 cells, and serum exosomes of MM patients harbored high level of circ-CACNG2. The clinical data analyses indicated that circ-CACNG2 was an independent prognostic and diagnostic indicator of MM-related cardiac complications. Also, in vitro experiments showed that circ-CACNG2 inhibited viability and promoted apoptosis of H9C2 cells. RIPA, pull-down assays, dual-luciferase reporter assays, and RNA FISH assays revealed that miR-197-3p could bind to circ-CACNG2 and caspase3 directly. Rescue experiments proved that circ-CACNG2 can increase the expression of caspase3 by binding to and decreasing the expression of miR-197-3p. In conclusion, MM-exosomes could inhibit cardiomyocyte viability and promote apoptosis partially through circ-CACNG2/miR-197-3p/caspase3 axis.

MAGE-a Inhibits Apoptosis in Multiple Myeloma through Regulation of Bim and PUMA

MAGE-a Inhibits Apoptosis in Multiple Myeloma through Regulation of Bim and PUMA

Retraction: Long noncoding RNA TUG1 promotes proliferation and inhibits apoptosis in multiple myeloma by inhibiting miR-29b-3p.

This article is being retracted from Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the authors to the duplication of Figure 2C, which appears in serval other publications by different authors.The authors wish to retract the article. The Editor-in-Chief and Editorial Board agree with the Retraction.

Retraction: Long noncoding RNA TUG1 promotes proliferation and inhibits apoptosis in multiple myeloma by inhibiting miR-29b-3p

Retraction: Long noncoding RNA TUG1 promotes proliferation and inhibits apoptosis in multiple myeloma by inhibiting miR-29b-3p

MicroRNA miR-188-5p as a mediator of long non-coding RNA MALAT1 regulates cell proliferation and apoptosis in multiple myeloma

ABSTRACT Multiple myeloma (MM), a malignancy of plasma cells mainly derived from the bone marrow, has remained incurable generally. LncRNA MALAT1 has been reported to be upregulated in the MM cells and knockdown of MALAT1 inhibited MM cell cycle progression and enhanced cell apoptosis. Online target prediction showed that two target sites for MALAT1 existed in miR-188-5p, which has been identified as a tumor suppressor in other types of cancers. However, the role of miR-188-5p in the MM and whether miR-188-5p mediates the MM tumor progression regulated by MALAT1 are still unknown. Herein, four main MM cell lines were adopted to investigate the effects of miR-188-5p on cell proliferation and apoptosis via transfection with miR-188-5p mimic/inhibitor and co-transfection with miR-188-5p inhibitor and MALAT1-shRNA plasmids. Xenograft tumor model was also established to study these effects in vivo. Overexpression of miR-188-5p inhibited cell viability, cell proliferation as well as tumor growth and arrested cell cycle at G1 to S transition, but miR-188-5p knockdown showed opposite effects on the MM cells in vitro and in vivo. Moreover, MALAT1 was shown to be inversely correlated with miR-188-5p expression through direct binding to miR-188-5p, and in turn, miR-188-5p could mediate the MM cell proliferation and apoptosis regulated by MALAT1. These findings indicate that miR-188-5p serves as a tumor suppressor in the progression of the MM and is directly involved in MM cell proliferation and apoptosis regulated by MALAT1, which may provide a potential therapeutic target or prognostic indictor for MM clinical treatment.

MiR-379 inhibits proliferation and induces apoptosis in multiple myeloma by targeting Y-box binding protein 1

Purpose: To determine the effect of miR-379 in multiple myeloma.Methods: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression of miR-379 in multiple myeloma cells. The effect of miR-379 on multiple myeloma progression was investigated by cell counting, bromodeoxyuridine staining, flow cytometry and Western blot analysis. A potential target for miR-379 was determined using a luciferase reporter assay.Results: MiR-379 expression was reduced in multiple myeloma cells, while over-expression of miR-379 increased both cell viability and proliferation of these cells (p &lt; 0.05). Moreover, miR-379 blocked cell cycle multiple myeloma cells and promoted apoptosis by decreasing Bcl-2 expression, and increasing the expression of cleaved caspase-3 and Bax. MiR-379 bound to Y-box binding protein 1 (YBX1) and reduced YBX1 mRNA and protein expression in multiple myeloma cells (p &lt; 0.05).Conclusion: A YBX1-mediated tumor-suppressive role for miR-379 in multiple myeloma cells has been identified, suggesting a potential strategy for the treatment of multiple myeloma.&#x0D; Keywords: MiR-379, Y-box binding protein 1, Multiple myeloma, Proliferation, Apoptosis

Updated analysis of a phase I/II study of venetoclax in combination with daratumumab and dexamethasone, +/- bortezomib, in patients with relapsed/refractory multiple myeloma.

8511 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells in vitro. It has shown synergistic activity with bortezomib (V) and dexamethasone (d). Combination of the CD38 monoclonal antibody daratumumab (D) with Ven is hypothesized to further increase anti-myeloma activity based on dual mechanisms of pro-apoptotic effects on tumor cells and enhanced immune stimulation. Methods: This ongoing Phase 1/2, nonrandomized, multicenter study (NCT03314181) is evaluating safety, efficacy and pharmacokinetics (PK) of VenDd +/- V in patients (pts) with relapsed/refractory MM. In Part 1, pts with t(11;14) who received ≥1 prior line of therapy (PI and an immunomodulatory drug) were treated with VenDd [Ven QD + D 16 mg/kg IV + d 40 mg weekly]. In Part 2, pts irrespective of t(11;14) status, non-refractory to PIs and who received 1–3 prior lines of therapy were treated with VenDVd [Ven QD + D 16 mg/kg IV + V (1.3 mg/m2) + d (20 mg)]. A randomized, open-label expansion (Part 3) will further evaluate and compare safety and efficacy of VenDd (400 or 800 mg Ven dose levels) with control DVd in pts with t(11;14). Results: As of Dec 05, 2019, 48 pts were enrolled. Part 1 included 24 pts with t(11;14), median age 63 (range 51–76). Part 2 included 24 pts, median age 65 (range 41–80) of which 6 (25%) had t(11;14). Frequent adverse events (AEs; VenDd/VenDVd) were fatigue (71%/25%), diarrhea (58%/46%), nausea (46%/50%), insomnia (33%/50%), upper respiratory tract infection (33%/21%), cough (42%/9%), and dyspnea (25%/25%). Frequent Grade ≥ 3 AEs in pts on VenDd were neutropenia (17%), hypertension (12%), fatigue and hyperglycemia (8% each), and in pts on VenDVd were insomnia (21%), diarrhea and thrombocytopenia (8% each). Nine pts had infection-related Grade ≥ 3 AEs (5 VenDd, 4 VenDVd). Eighteen pts had a serious AE (11 VenDd, 7 VenDVd) with pyrexia (n = 3) being most common. One pt on VenDVd died of progressive disease. PK analyses showed that addition of D and V did not impact Ven exposure. Median follow-up time (VenDd/VenDVd) was 10 and 9 months. Overall response rate in VenDd/VenDVd was 96%/92% and 96%/79% had ≥ very good partial response rate. Median progression free survival and duration of response were not reached. Conclusions: Pts treated with VenDd +/- V continue to demonstrate a tolerable safety profile with encouraging efficacy, notably among pts with t(11;14) treated with VenDd. Safety, efficacy, PK, and cytogenetics analyses will be updated for presentation. Clinical trial information: NCT03314181 .

PSAT1 prompted cell proliferation and inhibited cell apoptosis in multiple myeloma through regulating PI3K/AKT pathway

Purpose: To identify the biological function of phosphoserine aminotransferase 1 (PSAT1) in regulating cell proliferation and apoptosis in multiple myeloma (MM).Methods: The mRNA and protein levels of PSAT1 were determined using quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell proliferation was measured using CCK-8 assay.Results: PSAT1 mRNA and protein expression levels were significantly increased in MM cell lines when compared to control cells. Moreover, downregulation of PSAT1 inhibited MM cell proliferation and induced cell apoptosis, whereas overexpression of PSAT1 promoted MM cell proliferation and suppressed cell apoptosis. Further analysis demonstrated that the underlying mechanism was via regulation of PI3K/AKT pathway.Conclusion: The results identified a novel role for PSAT1 in the progression of MM, which may provide a therapeutic and a new anticancer target for the therapy of MM.&#x0D; Keywords: Multiple myeloma, PSAT1, Cell proliferation, PI3K/AKT pathway

Long Noncoding RNA LUCAT1 Promotes Multiple Myeloma Cell Growth by Regulating the TGF-β Signaling Pathway.

Objective:Long noncoding RNAs (lncRNAs) are potential biomarkers for cancers. Nevertheless, the ability of long noncoding RNA lung cancer-associated transcript 1 in patients with multiple myeloma remains unknown. The purpose of this current study was to figure out its function in multiple myeloma.Methods:Firstly, the expression of long noncoding RNA lung cancer-associated transcript 1 in cancer or normal tissues and serum from patients with multiple myeloma and normal donors was detected. Secondly, the expression of long noncoding RNA lung cancer-associated transcript 1 was overexpressed or silenced in U266 and H929 cells, respectively to detect changes of proliferation and apoptosis in multiple myeloma in vitro. Subsequently, the expression of transforming growth factor-β signaling pathway-related proteins was detected by western blot analysis. Finally, the effect of long noncoding RNA lung cancer-associated transcript 1 on the growth of multiple myeloma cells in vivo was evaluated by tumor xenograft in nude mice.Results:Long noncoding RNA lung cancer-associated transcript 1 was increased in cancer tissues and serum of patients with multiple myeloma as well as multiple myeloma cells, which was correlated with dismal prognosis of patients with multiple myeloma. Overexpression of long noncoding RNA lung cancer-associated transcript 1 promoted the activity of U266 and H929 cells, while inhibition of long noncoding RNA lung cancer-associated transcript 1 suppressed the activity of U266 and H929 cells. In addition, long noncoding RNA lung cancer-associated transcript 1 was found to promote activation of the transforming growth factor-β signaling pathway. Furthermore, long noncoding RNA lung cancer-associated transcript 1 knockdown restricted the growth of multiple myeloma cells in vivo.Conclusion:This study suggests that suppression of long noncoding RNA lung cancer-associated transcript 1 inhibits the activation of transforming growth factor-β signaling pathway, thereby inhibiting the growth of multiple myeloma cells.

CIAPIN1 is a potential target for apoptosis of multiple myeloma

This study firstly aimed to reveal the gene expression differences of CIAPIN1 between myelomas cells from bone marrow cells of multiple myeloma patients and normal human, and subsequently investigate the regulation role of this gene on tumorigenicity ability of multiple myeloma (MM) cell line U266 via in vitro colony formation and in vivo xenograft studies. RT-PCR results obtained from 18 MM patients and 10 health people showed that the expression of CIAPIN1 gene was 4 times higher in normal human compared to MM patients. Besides, CIAPIN1 siRNA (si-CIAPIN1) transfected U266 cells presented higher proliferation ratio and superior colony forming ability than U266 cells and U266 cells transfected with non-coding siRNA (controls) evaluated by CCK8 test and soft agar colony formation assay, respectively. In a mice MM xenograft model, the si-CIAPIN1 transfected U266 cells induced the biggest tumor compared to the controls. Furthermore, CIAPIN1 overexpressed U266 cells were developed and compared with the si-CIAPIN1 transfected U266 cells to study the role of CIAPIN1 in the production of apoptosis related proteins in U266 cells. Results indicated that CIAPIN1 facilitated apoptosis promoting proteins expression in U266 cells, such as upregulation of BAX, BAK, Bcl-xs and BIM, and downregulation of p38, PKC, Bcl-2 and Bcl-xl proteins. Therefore, CIAPIN1 can be a potential suppression target gene in multiple myeloma.

Targeting CD47/TNFAIP8 by miR-155 overcomes drug resistance and inhibits tumor growth through induction of phagocytosis and apoptosis in multiple myeloma.

The mechanisms of drug resistance in multiple myeloma (MM) are poorly understood. Here we show that CD47, an integrin-associated receptor, is significantly up-regulated in drug resistant myeloma cells in comparison with parental cells, and that high expression of CD47 detected by immunohistochemistry is associated with shorter progression-free and overall survivals in MM patients. We show that miR-155 is expressed at low levels in drug resistant myeloma cells and is a direct regulator of CD47 through its 3´UTR. Furthermore, low miR-155 levels are associated with advanced stages of disease. MiR-155 overexpression suppressed CD47 expression on myeloma cell surface, leading to induction of phagocytosis of myeloma cells by macrophages and inhibition of tumor growth. MiR-155 overexpression also re-sensitized drug-resistant myeloma cells to bortezomib leading to cell death through targeting TNFAIP8, a negative mediator of apoptosis in vitro and in vivo. Thus, miR-155 mimics may serve as a promising new therapeutic modality by promoting phagocytosis and inducing apoptosis in patients with drug-refractory/relapsed MM.

Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma