Gene expression signatures in FAM46C (TENT5C)-deleted multiple myeloma (MM) cell lines
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ABSTRACT:
PROVIDER: PRJNA489271 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the effect of FAM46C disruption on gene expression, we generated FAM46C-knockout (FAM46C-KO) cell clones using CRISPR/Cas9 system with MM cell lines OCI-My5, KMS-11, and ANBL-6. Using the generated cell clones, we have employed whole genome microarray expression profiling as a discovery platform to identify genes that are associated with FAM46C expression in MM cell lines. OCI-My5, KMS-11, and ANBL-6 cell clones were cultured for 48 h in vitro.
2018-09-05 | GSE119451 | GEO
Project description:FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
2017-07-26 | GSE99356 | GEO
Project description:FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
2017-07-26 | GSE99357 | GEO
Project description:FAM46C is one of the most frequently mutated genes in multiple myeloma (MM). Here, using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active non-canonical poly(A) polymerase which enhances mRNA stability and gene expression. Reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induces cell death. Moreover, silencing of FAM46C in MM cells expressing WT protein enhance cell proliferation. Finally, using a FAM46C-FLAG knock-in mouse strain we show that the FAM46C protein is strongly induced during activation of primary splenocytes and that B lymphocytes isolated from newly generated FAM46C KO mice proliferate faster than those isolated from their WT littermates. Concluding, our data clearly indicate that FAM46C works as an onco-suppressor, with the specificity for B-lymphocyte lineage from which multiple myeloma originates.
2018-03-09 | PXD006790 | Pride
Project description:FAM46C, which is frequently mutated in multiple myeloma (MM), has recently been shown to encode a non-canonical poly(A) polymerase (ncPAP). However, its target mRNAs and its role in MM pathogenesis remain largely unknown. Using CRISPR-Cas9 technology and gene expression analysis we found that inactivation of FAM46C in MM downregulates immunoglobulins (Igs) and several mRNAs encoding ER-resident proteins, including some involved in unfolded protein responses (UPRs), such as PDIA6, ERP44 and EDEM2, and others that affect glycosylation, such as SSR4, AGA and DDOST. We show that FAM46C expression is induced during PC differentiation and that Ig mRNAs encoding heavy and light chains are direct substrates of the ncPAP, as revealed by poly(A) tail-length determination assays. The absence of the ncPAP results in Ig mRNA poly(A) tail-shortening, leading to a reduction in mRNA and protein abundance. On the other hand, loss of FAM46C upregulates metastasis-associated lncRNA MALAT1 and results in a sharp increase in the migration ability of MM cells. This phenotype depends mainly on the activation of PI3K/Rac1 signaling in FAM46C knockout cells since treatment with specific inhibitors substantially reduces cell mobility. This finding may have significant therapeutic implications. In conclusion, our results identify Ig mRNAs as targets of FAM46C, reveal an important function of this protein during PC maturation to increase antibody production, and show that its inactivation in MM increases cell migration and invasion, which might explain the poor prognosis of MM patients with FAM46C alterations and its role as a tumor suppressor.
2020-04-10 | GSE114984 | GEO
Project description:FAM46C is one of the most frequently mutated genes in multiple myeloma (MM) and encodes a protein of unknown function. Using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active cytoplasmic non-canonical poly(A) polymerase, which enhances mRNA stability and gene expression. Moreover, we also found that the reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induced cell death. This is, to our knowledge, the first report that directly associates cytoplasmic poly(A) polymerase with carcinogenesis. Furthermore, our data suggest that the human genome encodes at least eleven non-canonical poly(A) polymerases with four FAM46 family members. Since FAM46 proteins are differentially expressed during development, these proteins may positively regulate transcript stability and translational rate in a tissue-specific manner.
2017-06-30 | GSE83772 | GEO
Project description:The aim of the analysis is to compare the trascriptome of myeloma cells expressing the wt version of novel oncosuppressor FAM46C comparing it with that of cells expressing a mutant variant of the same gene often found in patients (the D90G mutant allele) or to a Mock control. Cells were grown in RPMI media at 500000 cells/ml. After 4 days of culture total RNA was extracted.
2020-10-23 | E-MTAB-8188 | biostudies-arrayexpress
Project description:Endoplasmic reticula (ER) were isolated from LP1 human myeloma cells expressing either the wt FAM46C protein or the D90G mutant version, which is often found in myeloma patients. RNAs were purified from the ER and sequenced. Quantitation and characterization of specifically ER-bound mRNAs is important in determining the secretomic potential of cells. In this case we focused on comparing cells expressing the two forms of the FAM46C protein in the LP1 cell line which lacks FAM46C expression.
2020-10-22 | E-MTAB-8497 | biostudies-arrayexpress
Project description:The role of FAM46C in myeloma cells
| PRJNA388191 | ENA
Project description:The objective of this study is to identify genes involved in the pathogenesis of multiple myeloma (MM). In this study, we performed gene expression profiling of a total of 29 samples consisting of 19 clinical specimens, 7 myeloma cell lines and 3 normal samples. The microarray data were analysed by GeneSpring Software v14.9. A total of 5124 DEGs were identified in MM group vs control group (fold change≥2.0; P<0.05). Out of 5124 DEGs, 2696 and 2428 genes were up-regulated and down-regulated, respectively in MM group compared to the normal control group.
2022-07-20 | GSE72213 | GEO