Role of plasma EBV-DNA load and EBER status on newly diagnosed peripheral T-cell lymphoma.

PURPOSE: To explore the prognostic and therapeutic role of Epstein-Barr Virus (EBV) on peripheral T-cell lymphoma (PTCL). METHODS: Totally 262 newly diagnosed PTCL patients who were hospitalized from January 2014 to December 2022 were retrospectively enrolled. Molecular analysis included 31 eligible patients. EBV-encoded RNA (EBER) presence in tumor tissue and EBV DNA levels in patients at baseline (DNA1) and after 4 cycles of chemotherapy (DNA4) were assessed. RESULTS: Our findings revealed that the EBER-positive cohort exhibited significant differences compared to counterparts in overall survival (OS, P = 0.047) and progression-free survival (PFS, P = 0.009). Both DNA1 and DNA4 were significantly associated with inferior OS. Multivariate analysis demonstrated that DNA4 independently affected PTCL prognosis for OS (hazard ratio = 5.1617; 95% confidence interval 1.1017-24.1831; P = 0.037). Treatment with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus azacytidine regimen showed a better OS compared to CHOP or CHOP plus etoposide for patients with partially positive EBER and EBER positive statuses (P = 0.192), although the improvement was not statistically significant. This study delineated the genetic paradigm of PTCL, comparing genetic differences by EBV status and found that EBER partially positive plus positive patients were more likely to have DNMT3A (P = 0.002), RHOAG17V (P = 0.023), and TET2 mutations (P = 0.032). CONCLUSION: EBER, DNA1, and DNA4 emerged as sensitive markers for prognosis. CHOP plus azacytidine might present a preferable option for PTCL patients with DNA methylation due to EBV infection.

The ratio of serum urea nitrogen to albumin is a better predictor of OS in MM patients than urea nitrogen alone.

Introduction Multiple myeloma (MM) is a malignant proliferative disease of plasma cells. Abnormally cloned plasma cells secrete large amounts of monoclonal immunoglobulins in the bone marrow of MM patients. Serum urea nitrogen (sUN) is a byproduct of protein metabolism, and its effect on MM patients' prognoses remains unknown. Therefore, we analysed MM patients' clinical data to explore the role of sUN and serum urea nitrogen/serum albumin (sUAR) in the baseline tumor load and MM prognosis of MM patients. Methods We downloaded the clinical data of 762 MM patients from the MMRF database. After excluding those without baseline sUN, 452 patients were finally included in the study. Smoothed curve fitting, threshold analysis, Tamhane's T2 test, multivariate adjusted Cox regression analysis, Kaplan‒Meier (K-M) curves, and receiver operating characteristic (ROC) analysis were applied in the study. Results There were 452 newly diagnosed MM patients included in this study. In most patient groups, sUN and sUAR were positively linked with ß2-microglobulin (ß2-MG) and lactic dehydrogenase (LDH) according to smoothing curve fitting and threshold analysis. The higher the ISS stage, the greater the values of sUN and sUAR. Furthermore, smoothed curve fitting and threshold analysis showed that sUN was correlated with OS, although sUAR had a stronger correlation with OS and could be applied to a broader group. The results of a multivariate adjusted Cox regression analysis demonstrated that sUN and sUAR were independent prognostic factors for OS. The K-M curve confirmed the correlation between higher sUN and sUAR levels and worse OS. ß2-MG and LDH are generally recognized prognostic factors of OS. ROC analysis revealed that sUN might boost ß2-MG and LDH's predictive value and sUAR had a higher predictive value. Conclusion This retrospective study based on the MMRF database showed that high sUN and sUAR levels were positively associated with ß2-MG, LDH, and ISS staging, and sUAR exhibited a stronger correlation with OS than sUN alone.

C-C Motif Chemokine 2 Regulates Macrophage Polarization and Contributes to Myocardial Infarction Healing.

Macrophages are crucial immune cells that play essential roles in the healing of myocardial infarction (MI), undergoing continuous polarization throughout this process. C-C motif chemokine 2 (CCL2) is a chemokine that regulates inflammatory responses during MI. However, the extent to which CCL2 influences macrophage polarization and MI healing remains incompletely understood. In this study, we investigate the role of CCL2 in macrophage polarization and MI healing. Our findings reveal that CCL2 is differentially expressed in lipopolysaccharide (LPS)-induced M1 and interleukin (IL)-4-induced M2 RAW264.7 macrophages. Knockdown of CCL2 attenuates TNF-α secretion stimulated by LPS, while overexpression of CCL2 mitigates IL-10 production triggered by IL-4 in these macrophages. Moreover, CCL2 deficiency disrupts LPS-induced M1 polarization, whereas CCL2 overexpression reduces M2 polarization of RAW264.7 macrophages induced by IL-4. Further exploration indicates that the promotion of M1 polarization by CCL2 is significantly impaired by inhibition of the p38-mediated MAPK pathway and NF-κB pathway. In a MI mouse model, CCL2 knockdown remarkably reduces infarct size, collagen synthesis, and the expression of cardiac fibrosis and hypertrophy markers. The activity of the p38-mediated MAPK pathway and NF-κB pathway is downregulated by CCL2 knockdown as well. Additionally, the number of total macrophages and M1 macrophages in the infarct decreases, while the number of M2 macrophages increases upon CCL2 deficiency. In conclusion, these results suggest that CCL2 is a key regulator of macrophage polarization, controlling MI healing in vivo.

Assessing cell chimerism in an acute graft-versus-host disease model established in TLR4 knockout mice.

BACKGROUND: Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. OBJECTIVE: To elucidate the role of Toll-like receptor 4 (TLR4), the major receptor for bacterial lipopolysaccharide, in the development of GVHD, we constructed a GVHD model in TLR4 knockout (TLR4-/-) mice and monitored the cell chimerism. METHODS: In this study, we used polymerase chain reaction to identify whether TLR4 knockout (TLR4-/-) mice were established. Before transplantation, we pretreated mice with irradiation so as to obtain an appropriate irradiation dose. Flow cytometry was applied to measure the chimerism status, the distributions of antigen-presenting cells (APCs), and T-cells in TLR4+/+ and TLR4-/- recipient mice. RESULTS: The general condition of TLR4-/- recipients was better than that of TLR4+/+ recipients, and the TLR4-/- recipient mice showed less severe GVHD manifestations than the TLR4+/+ recipient mice. Most of the APCs and T-cells in the host mouse spleen were derived from donor cells, and CD4+ T-cells, including memory T-cells, were in the majority in host mice. CONCLUSION: In general, our data show that TLR4 deletion attenuated GVHD development, which suggests that TLR4 could be used as a novel target and therapeutic paradigm in GVHD therapies.

ANTECEDENTES: La enfermedad de injerto contra huésped (EICH) es una complicación importante después del trasplante alogénico de células madre hematopoyéticas. OBJETIVOS: Para dilucidar el papel de TLR4, el principal receptor de LPS bacteriano, en el desarrollo de GVHD, construimos un modelo de GVHD en ratones knockout para TLR4 (TLR4-/-) y monitoreamos el quimerismo celular. MÉTODOS: En este estudio, usamos PCR para identificar si se establecieron ratones knockout para TLR4 (TLR4-/-). Antes del trasplante, pretratamos a los ratones con irradiación para obtener la dosis de irradiación adecuada. Se aplicó citometría de flujo para medir el estado de quimerismo, las distribuciones de APC y células T en ratones receptores TLR4+/+ y TLR4-/-. RESULTADOS: El estado general de los receptores de TLR4-/- fue mejor que el de los receptores de TLR4+/+, y los ratones receptores de TLR4-/- mostraron manifestaciones de GVHD menos graves que los ratones receptores de TLR4+/+. La mayoría de las APC y las células T en el bazo del ratón huésped se derivaron de las células del donante, y las células T CD4+, incluidas las células T de memoria, se encontraban en su mayoría en los ratones huéspedes. CONCLUSIÓN: En general, nuestros datos muestran que la eliminación de TLR4 atenuó el desarrollo de GVHD, lo que sugiere que TLR4 podría usarse como un nuevo objetivo y paradigma terapéutico en las terapias de GVHD.

[Efficacy and Safety of Plerixafor Combined with G-CSF for Autologous Peripheral Blood Hematopoietic Stem Cell Mobilization in Lymphoma Patients].

OBJECTIVE: To investigate the efficacy and safety of plerixafor combined with granulocyte colony-stimulating factor (G-CSF) in mobilizing peripheral blood hematopoietic stem cells in patients with lymphoma. METHODS: The clinical data of lymphoma patients who received autologous hematopoietic stem cell mobilization using plerixafor combined with G-CSF from January 2019 to December 2021 were retrospectively analyzed. The patients received 3 kinds of mobilization regimens: front-line steady-state mobilization, preemptive intervention, and recuse mobilization. The acquisition success rate, excellent rate of collection, and incidence of treatment-related adverse reaction were counted. The influence of sex, age, disease remission status, bone marrow involvement at diagnosis, chemotherapy lines, number of chemotherapy, platelet count and number of CD34+ cells on the day before acquisition in peripheral blood on the collection results were analyzed to identify the risk factors associated with poor stem cell collection. RESULTS: A total of 43 patients with lymphoma were enrolled, including 7 cases who received front-line steady-state mobilization, 19 cases who received preemptive intervention, and 17 cases who received recuse mobilization. The overall acquisition success rate was 58.1% (25/43) after use of plerixafor combined with G-CSF, and acquisition success rate of front-line steady-state mobilization, preemptive intervention, and recuse mobilization was 100%, 57.9%(11/19), and 41.2%(7/17), respectively. The excellent rate of collection was 18.6%(8/43). A total of 15 patients experienced mild to moderate treatment-related adverse reactions. The number of CD34+ cells < 5 cells/µl in peripheral blood on the day before collection was an independent risk factor affecting stem cell collection. CONCLUSIONS: Plerixafor combined with G-CSF is a safe and effective mobilization regimen for patients with lymphoma. The number of CD34+ cells in peripheral blood on the day before collection is an predictable index for the evaluation of stem cell collection.

CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest. / EGFR和HDAC双靶点抑制剂CUDC-101通过调控G2/M期阻滞增强硼替佐米抗骨髓瘤的作用.

CUDC-101, an effective and multi-target inhibitor of epidermal growth factor receptor (EGFR), histone deacetylase (HDAC), and human epidermal growth factor receptor 2 (HER2), has been reported to inhibit many kinds of cancers, such as acute promyelocytic leukemia and non-Hodgkin's lymphoma. However, no studies have yet investigated whether CUDC-101 is effective against myeloma. Herein, we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma (MM) cell lines and induces cell apoptosis in a time- and dose-dependent manner. Moreover, CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase (PI3K) and HDAC, and regulated the cell cycle G2/M arrest. Moreover, we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug. Bortezomib is one of the important drugs in MM treatment, and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib. The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade. Collectively, our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib, which provides insights into exploring new strategies for MM treatment.

TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting prosurvival autophagy.

Bortezomib (bort) is an effective therapeutic agent for patients with multiple myeloma (MM); however, most patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis, and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif-containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, whereas TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phosphoproteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated prosurvival autophagy. Our results showed that TRIM21 KD MM cell lines induced prosurvival autophagy after bort treatment, suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of autophagy-related gene 5 (ATG5)-restored-bort sensitivity. Indeed, ATG5 expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the antimyeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approach.

Liquid biopsy by analysis of circulating myeloma cells and cell-free nucleic acids: a novel noninvasive approach of disease evaluation in multiple myeloma.

Multiple myeloma (MM) is an incurable hematological cancer with high spatial- and temporal-heterogeneity. Invasive single-point bone marrow sampling cannot capture the tumor heterogeneity and is difficult to repeat for serial assessments. Liquid biopsy is a technique for identifying and analyzing circulating MM cells and cell products produced by tumors and released into the circulation, allowing for the minimally invasive and comprehensive detection of disease burden and molecular alterations in MM and monitoring treatment response and disease progression. Furthermore, liquid biopsy can provide complementary information to conventional detection approaches and improve their prognostic values. This article reviewed the technologies and applications of liquid biopsy in MM.

Calcium silicate/bortezomib combinatory therapy for multiple myeloma.

Multiple myeloma (MM) is the second most common hematologic malignancy. Bortezomib (BOR), a first-generation proteasome inhibitor, is the basic agent for the treatment of MM and has greatly improved the survival of patients with MM. However, the side effects of BOR (e.g. peripheral neuropathy) occur frequently and almost all MM patients eventually develop resistance to BOR and go on to develop refractory relapsed multiple myeloma (RRMM). Therefore, it is of great significance to find a method to increase the sensitivity of MM to BOR to reduce toxicity and drug resistance. Herein, we found that calcium silicate (CS), a silicate bioceramic that releases Si ions (SIs), enhanced the BOR anti-myeloma effect in vitro in human myeloma cell lines (HMCLs), including BOR-resistant cell lines (U266/BOR). The enhanced anti-myeloma effect of these two agents was demonstrated in primary MM cells regardless of disease status and in MM xenograft mice. Mechanistically, SI enhanced G2/M cell cycle arrest and the inhibition of the NF-κB pathway induced by BOR. These results imply that the combination of SI and BOR (SI/BOR) is a promising way to overcome BOR resistance in MM and RRMM. The future use of nanotechnology to prepare CS nanomaterials as BOR carriers for the treatment of MM and RRMM is a very promising clinical application.

The efficacy of residual plerixafor for second-day stem cell mobilization in multiple myeloma patients.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) plus plerixafor has been shown to improve the efficacy of peripheral blood stem cell (PBSC) mobilization, however, due to its high price, the use of plerixafor is limited in China. The purpose of this study was to assess the efficacy of residual plerixafor for second-day stem cell mobilization in multiple myeloma (MM) patients. MATERIALS AND METHODS: In this single-center retrospective study, 69 MM patients received G-CSF + plerixafor to mobilize PBSCs, which were collected from 28 patients only for one day and 41 patients for two days. Some of the patients received residual plerixafor, and PBSCs were collected on the second day. The data on the characteristics, different doses of plerixafor and efficacy of PBSC mobilization were collected and analyzed. RESULTS: After 1 or 2 apheresis procedures, 85.5% of patients collected more than 2 × 106 cells/kg PBSCs. There was no statistically significant difference in the success rate of CD34 + PBSC mobilization with the different doses of plerixafor on the first day, but the higher residual plerixafor dose resulted in better success rates on the second day (P＜0.001). Among the patients who collected PBSCs for two days, the level of the CD34 + cell yield of 24 patients (58.5%) changed better, which was significantly correlated with the dose of residual plerixafor on the second day (P = 0.001). DISCUSSION: These results suggested that the administration of residual plerixafor to mobilize stem cells on the second day is an economical, efficient and clinically feasible method.

Interleukin-32γ promotes macrophage-mediated chemoresistance by inducing CSF1-dependent M2 macrophage polarization in multiple myeloma.

Macrophages (MΦs) are an abundant component in the multiple myeloma (MM) environment and contribute to MM drug resistance. We previously showed that interleukin-32 (IL-32) is highly expressed in MM patients and induces the immunosuppressive function of MΦs. The present study was designed to explore the role of IL-32 in MΦ-mediated MM drug resistance and the underlying mechanism. Our analysis revealed that IL-32 expression was upregulated in relapsed MM patients and associated with CD206+ M2 MΦ infiltration. Subsequently, we found that the most active isoform, IL-32γ, promoted MΦs to protect MM cells from drug-induced apoptosis both in vitro and in vivo. Furthermore, by evaluating many parameters, including surface markers, cytokines, metabolic enzymes and characteristic molecules, IL-32γ was verified to induce the polarization of M2 MΦs, a function that was partly dependent on increasing the expression of colony-stimulating factor 1 (CSF1). Taken together, the results of our study indicate that IL-32γ promotes MΦ-mediated MM drug resistance and modifies MΦs toward the M2 phenotype, providing a crucial theoretical basis for targeted MΦ immunotherapy.

High levels of serum IL-10 indicate disease progression, extramedullary involvement, and poor prognosis in multiple myeloma.

Multiple myeloma (MM) is a common malignant hematological tumor in adults, which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins (M protein), leading to bone destruction, hypercalcemia, anemia, and renal insufficiency (Alexandrakis et al., 2015; Yang et al., 2018). Since a large number of new drugs, represented by proteasome inhibitors and immunomodulators, have been successfully used to treat MM, treatment efficacy and survival of patients have been significantly improved. However, due to the high heterogeneity of this disease, patients have responded differently to treatments with these new drugs (Palumbo and Anderson, 2011; Wang et al., 2016; Huang et al., 2020). Growth and survival of MM cells depend on the bone marrow microenvironment, especially numerous inflammatory cytokines secreted by myeloma cells and bone marrow stromal cells, such as vascular endothelial growth factor (VEGF), interleukin (IL)|-6, transforming growth factor-|ß (TGF||-||ß), and IL-10. These cytokines can promote the growth of myeloma cells, induce angiogenesis, and inhibit antitumor immunity, and are often linked to patient prognosis (Kumar et al., 2017). In this era of new drugs, the prognostic values of the serum levels of these cytokines in MM need further evaluation.

Chidamide and venetoclax synergistically exert cytotoxicity on multiple myeloma by upregulating BIM expression.

BACKGROUND: Multiple myeloma (MM) is the second most common hematologic malignancy with almost all patients eventually having relapse or refractory MM (RRMM), thus novel drugs or combination therapies are needed for improved prognosis. Chidamide and venetoclax, which target histone deacetylase and BCL2, respectively, are two promising agents for the treatment of RRMM. RESULTS: Herein, we found that chidamide and venetoclax synergistically exert an anti-myeloma effect in vitro in human myeloma cell lines (HMCLs) with a combination index (CI) < 1. Moreover, the synergistic anti-myeloma effect of these two drugs was demonstrated in primary MM cells and MM xenograft mice. Mechanistically, co-exposure to chidamide and venetoclax led to cell cycle arrest at G0/G1 and a sharp increase in DNA double-strand breaks. In addition, the combination of chidamide and venetoclax resulted in BCL-XL downregulation and BIM upregulation, and the latter protein was proved to play a critical role in sensitizing HMCLs to co-treatment. CONCLUSION: In conclusion, these results proved the high therapeutic potential of venetoclax and chidamide combination in curing MM, representing a potent and alternative salvage therapy for the treatment of RRMM.

Myeloma-derived IL-32γ induced PD-L1 expression in macrophages facilitates immune escape via the PFKFB3-JAK1 axis.

Multiple myeloma (MM) is characterized by an accumulation of monoclonal plasma cells within the bone marrow (BM). Macrophages are an abundant component of myeloma BM microenvironment and support survival of the malignant cells and foster myeloma development and progression by suppression of the immune response. In our previous study, we found that MM patients overexpress pro-inflammatory cytokine interleukin-32 (IL-32). The present study aimed to investigate the role of IL-32 in myeloma progression and mechanisms of IL-32 on macrophages functions. We discovered that the expression of IL-32 was associated with the disease stage in myeloma patients. MM-derived exosomes containing IL-32γ promoted the expression of programmed death-ligand 1(PD-L1) by macrophages, thus promoting immune evasion. Mechanistically, myeloma-secreted IL-32γ acted via proteinase 3 (PR3) to enhance 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) dependent glycolysis and subsequent PD-L1 expression. Moreover, the PFKFB3-Janus kinase 1 (JAK1) axis might contribute to the expression of PD-L1 by macrophages. To sum up, we concluded that IL-32 was a critical mediator in myeloma progression, and targeting IL-32 signaling might be used as a potential strategy for treating myeloma.

NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma.

Multiple myeloma (MM) remains an incurable plasma cell cancer characterized by abnormal secretion of monoclonal immunoglobulins. The molecular mechanism that regulates the drug sensitivity of MM cells is being intensively studied. Here, we report an unexpected finding that the protein encoded by neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L), which is a HECT E3 ligase, binds the 19S proteasome, limiting its proteolytic function and enhancing autophagy. Suppression of NEDD4L expression reduced bortezomib (Bor) sensitivity in vitro and in vivo, mainly through autophagy inhibition mediated by low NEDD4L expression, which was rescued by an autophagy activator. Clinically, elevated expression of NEDD4L is associated with a considerably increased probability of responding to Bor, a prolonged response duration, and improved overall prognosis, supporting both the use of NEDD4L as a biomarker to identify patients most likely to benefit from Bor and the regulation of NEDD4L as a new approach in myeloma therapy.

RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential.

RNA demethylase ALKBH5 takes part in the modulation of N6-methyladenosine (m6A) modification and controls various cell processes. ALKBH5-mediated m6A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m6A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies.

The adverse impact of a gain in chromosome 1q on the prognosis of multiple myeloma treated with bortezomib-based regimens: A retrospective single-center study in China.

Background: Multiple myeloma is genetically heterogeneous, and chromosome abnormalities play a pivotal role in prognosis. A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities; however, its relationship with overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma is still unclear. We aim to clarify the impact of +1q on the clinical characteristics and survival outcomes of patients treated with bortezomib-based combination regimes. Materials and methods: We retrospectively analyzed 258 patients first diagnosed with myeloma who underwent bortezomib-based therapy at the bone marrow transplantation department of a multiple myeloma treatment center in the first affiliated hospital of Zhejiang University, China. Results: We identified 258 newly diagnosed patients with multiple myeloma in our department from July 2013 to September 2018. We observed that 127 (49.2%) of the patients acquired +1q at diagnosis, and +1q strongly correlated with the occurrence of del(13q) and IgH rearrangement (P < 0.001). In the patients with +1q, the PFS was 22.2 months (95% CI 15.8-28.5 months), and the three-year and five-year PFS was 35.1% and 15.3%, respectively. Univariate analysis revealed that albumin, lactate dehydrogenase (LDH), and the percentage of plasma cells significantly affected PFS. Multivariate analysis showed that LDH and the percentage of plasma cells significantly affected PFS in the +1q patients. In terms of OS, the median OS for the +1q patients was 47.4 months (95% CI 34.7-59.5), while the OS of the non-+1q patients was not reached (P = 0.048). The univariate and multivariate analyses revealed that age, platelet count, and extramedullary lesions were significant adverse factors for OS in the +1q patients. There were no statistical differences between PFS and OS when there were other chromosomal abnormalities, but there was a decreased tendency in PFS. LDH and +1q also had a synergistic adverse effect on survival. Conclusion: +1q is associated with a higher tumor burden and correlated with the occurrence of del(13q) and IgH rearrangement at diagnosis. In the era of novel agents, +1q still significantly affects PFS and OS.

RNA demethylase ALKBH5 promotes tumorigenesis in multiple myeloma via TRAF1-mediated activation of NF-κB and MAPK signaling pathways.

N6-methyladenosine (m6A), an internal modification in mRNA, plays a critical role in regulating gene expression. Dysregulation of m6A modifiers promotes oncogenesis through enzymatic functions that disrupt the balance between the deposition and removal of m6A modification on critical transcripts. However, the roles of mRNA m6A in multiple myeloma (MM) are poorly understood. The present study showed that RNA demethylase ALKBH5 was overexpressed in MM and associated with a poor prognosis in MM patients. Knocking down ALKBH5 induced apoptosis and inhibited the growth of MM cells in vitro. Xenograft models and gene set enrichment analysis with patient transcriptome datasets also supported the oncogenic role of ALKBH5 in MM. Mechanistic studies showed that ALKBH5 exerted tumorigenic effects in myeloma in an m6A-dependent manner, and TNF receptor-associated factor 1 (TRAF1) was a critical target of ALKBH5. Specifically, ALKBH5 regulated TRAF1 expression via decreasing m6A abundance in the 3'-untranslated region (3'-UTR) of TRAF1 transcripts and enhancing TRAF1 mRNA stability. As a result, ALKBH5 promoted MM cell growth and survival through TRAF1-mediated activation of NF-κB and MAPK signaling pathways. Collectively, our data demonstrated that ALKBH5 played a critical role in MM tumorigenesis and suggested that ALKBH5 could be a novel therapeutic target in MM.

Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma.

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma. SIGNIFICANCE: A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets.

Corrigendum: Different Patient Subgroup Different Maintenance, Proteasome Inhibitors or Immunomodulators Maintenance for Newly Diagnosed Multiple Myeloma: A 7-Year Single-Center Data in China.

[This corrects the article DOI: 10.3389/fonc.2021.665217.].