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Project description:LILRB4 regulates multiple myeloma development through STAT3-PFKFB1 pathway
| PRJNA1137918 | ENA
Project description:Although multiple myeloma (MM) responds well to immunotherapeutic treatment, certain portions of MM are still unresponsive or relapse after immunotherapy. Other immune molecules are needed for the immunotherapy of MM. Here, we revealed that leukocyte immunoglobulin-like receptor B4 (LILRB4) was highly expressed in multiple myeloma cell lines and patient samples and that the expression of LILRB4 was adversely correlated with the overall survival of MM patients. Knockdown of LILRB4 efficiently delayed the growth of MM cells both in vitro and in vivo. Mechanistically, IKZF1 transactivated LILRB4 expression to trigger the downstream of STAT3-PFKFB1 pathways to support MM cell proliferation. Blockade of LILRB4 signaling by blocking antibodies can effectively inhibit MM progression. Our data show that targeting LILRB4 is potentially an additional therapeutic strategy for the immunotherapeutic treatment of MM.
| S-EPMC11258265 | biostudies-literature
Project description:SCG2 functionally interacts with leukocyte Ig-like receptor subfamily B4 (LILRB4) on monocytic cells. M-MDSCs were isolated from tumor bearing WT, LILRB4+/+ or LILRB4+/+ SCG2-/- mice for RNA-seq. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 replicates from each group.
2025-01-07 | GSE285725 | GEO
Project description:Purpose: to identify new potential pathways and therapeutic targets to kill plasma cells and affect their microenvironment in stage R-ISS III MM patients. Methods: We performed single-cell RNA sequencing of bone marrow samples obtained from nine MM patients and from two normal controls including pseudotime analysis, SCENIC analysis,cell–cell communication networks,large-scale chromosomal CNV analysis.The new markers that we reported originally were verified by qPCR, flow cytometry and immunofluorescence staining. Results: We identified two R-ISS-related modules, namely, “protein metabolism” (module 2) and “cell proliferation” (module 1). The gene expression pattern in pseudotime suggested that the gene activation in module 2 provides a substantial basis for the malignant proliferation of plasma cells during MM progression. We found that STAT1 may activate LETM1 to promote MM progression via the C-type lectin receptor signaling pathway. And PDIA6 was putatively activated by the UQCRB regulon to participate in oxidative phosphorylation. Moreover, a subcluster of monocytes exclusively found in stage III and specifically expressed CCL3L1, CCL3, and CXCL2 was modulated by ATF3. CCL3/CCL5/CCL3L1–CCR1, CCL4–SLC7A1, CD47–SIPRA, SEMA4A–PLXND1, and LILRB4–LAIR1 were identified as the active ligand–receptor pairs in plasma–monocyte communications in stage III. Conclusions: we systematically analyzed the molecular events and the regulated networks in the progression of the R-ISS stages, and the results suggested a promising landscape for the treatment of MM.
2022-11-30 | GSE176131 | GEO
Project description:Proteasome inhibitor bortezomib (BTZ) induces apoptosis in myeloma (MM) cells, and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine MM models, we here show that BTZ also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin (CALR) on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a BTZ-triggered specific ICD-gene signature which confers improved outcome in two independent MM patient cohorts. Importantly, BTZ stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate BTZ-induced ICD. Our studies therefore delineate mechanisms whereby BTZ exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with BTZ to induce potent tumor-specific immunity and improve patient outcome in MM.
2021-04-12 | GSE171837 | GEO
Project description:Epigenetic alterations play an important role in the pathogenesis in multiple myeloma (MM), but its biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for the survival of MM cells. Treatment with DOT1L inhibitors induced cell cycle arrest and apoptosis in MM cells, and strongly suppressed cell proliferation in vitro. Chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis revealed that DOT1L inhibition downregulated H3K79 dimethylation (H3K79me2) and expression levels of IRF4-MYC signaling genes in MM cells. Our data suggest that DOT1L may play an essential role in the development of MM, and DOT1L inhibition may provide a new therapy for MM treatment.
2018-09-23 | GSE108661 | GEO
Project description:Multiple myeloma (MM) is a malignant plasma cell disorder with well-defined clonal genetic/cytogenetic abnormalities. However, cellular heterogeneity is a key factor in MM’s progression, therapeutic decision, and response to treatment. Single cell whole transcriptome profiling (scRNA-Seq) offers an opportunity to dissect this molecular heterogeneity during MM progression to better understand the disease and guide rational therapy. Here, we examined 597 CD138 positive cells from 15 patients at different stages of MM progression using scRNA-Seq. We selected 790 genes based on a Coefficient of Variation (CV) approach which organized cells into four clusters (L1-L4) based on unsupervised clustering. Plasma cells from each patient contained a mixed population of plasma cells at different state of aggressiveness based on gene expression signature reflecting the inter-cellular heterogeneous nature of MM. Cells in the L1 group is characterized by low level expression of genes involved in the oxidative phosphorylation, Myc targets, and mTORC1 signaling pathway having most cells from MGUS patients (p < 1.2x10-14). In contrast, low level of these genes in L1 group increased progressively and were the highest in the L4 group containing only cells from high-risk MM patients with t(4;14) translocations. Furthermore, 44 genes consistently overexpressed by pair-wised comparisons of the four groups strongly associated with a reduced overall survival in MM patients (APEX trial, p < 0.0001; Hazard Ratio (HR), 1.83; 95% CI, 1.33 to 2.52), particularly those in the bortezomib treated group (p < 0.0001; HR, 2.00; 95% CI, 1.39 to 2.89). No survival significance was observed for the dexamethasone treated group. Our study at the resolution of single cells showed that there is a mixed population of cells in each patient at different stages of MM progression and these cells can be organized into four different subgroups (L1 to L4). Consistent overexpression of the 44 genes from L1 to L4 groups is associated with patient outcome and treatment response. Our results show that oxidative phosphorylation, Myc target, and mTORC1 signaling genes are significant pathways for MM progression and affect MM prognosis and treatment stratification.
2018-11-17 | GSE118900 | GEO
Project description:Aberrant activation of CAMKIIγ has been linked to leukemia and T-cell lymphoma, but not multiple myeloma (MM). The purpose of this study was to explore the role of CaMKIIγ in the pathogenesis and therapy of MM. In this study, we found that CaMKIIγ was aberrantly activated in human MM and its expression level was positively correlated with malignant progression and poor prognosis. Ectopic expression of CaMKIIγ promoted cell growth, colony formation, cell cycle progress and inhibited apoptosis of MM cell lines, whereas, knockdown of CAMKIIγ expression suppressed MM cell growth in vitro and in vivo. Mechanically, we observed that CaMKIIγ overexpression upregulated p-ERK and p-Stat3 levels and suppression of CaMKIIγ had opposite effects. CaMKIIγ is frequently dysregulated in MM and plays a critical role in maintaining MM cell growth through upregulating STAT3 signaling pathway. Furthermore, our preclinical studies suggest that CaMKIIγ is a potential therapeutic target in MM, and could be intervened pharmacologically by small-molecule berbamine analogues.
| S-EPMC7377902 | biostudies-literature
Project description:MYC is a major oncogenic driver of Multiple Myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof-of-principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC dependent cancers as well.
2015-07-21 | GSE71100 | GEO
Project description:Mutations involving the NFKB pathway are present in at least 17% of multiple myeloma (MM) tumors and 40% of MM cell lines (MMCL). These mutations, which are thought to be progression events, enable MM tumors to become less dependent on extrinsic bone marrow signals that activate NFKB. Studies on a panel of 50 MMCL provide some clarification of the mechanisms through which these mutations act and the significance of classical vs alternative activation of NFKB. First, only one mutation (NFKB2) selectively activates the alternative pathway, whereas several mutations (CYLD, NFKB1, TACI) selectively activate the classical pathway. However, most mutations affecting NIK level (NIK, TRAF2, TRAF3, cIAP1&2, CD40) activate the alternative but often both pathways. Second, we confirm the critical role of TRAF2 in regulating NIK degradation, whereas TRAF3 enhances but is not essential for cIAP1/2-mediated proteosomal degradation of NIK in MM. Third, using transfection to selectively activate the classical or alternative NFKB pathways, we show virtually identical changes in gene expression in one MMCL, whereas the changes are similar albeit non-identical in a second MMCL. Together, our results suggest that MM tumors can achieve increased autonomy from the bone marrow microenvironment by mutations that activate either NFKB pathway.
2009-09-11 | GSE18047 | GEO