Abstract
FAM46C, 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 mostly unknown. Using CRISPR‐Cas9 technology and gene expression analysis, we found that the inactivation of FAM46C in MM down‐regulates immunoglobulins (Igs) and several mRNAs encoding ER‐resident proteins, including some involved in unfolded protein response and others that affect glycosylation. Interestingly, we show that FAM46C expression is induced during plasma cell (PC) differentiation and that Ig mRNAs encoding heavy and light chains are 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 up‐regulates metastasis‐associated lncRNA MALAT1 and results in a sharp increase in the migration ability. This phenotype depends mainly on the activation of PI3K/Rac1 signalling, which might 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 suggest that its role as a tumour suppressor might be related to the inhibition of myeloma cell migration.
Highlights
Multiple myeloma (MM), the second most common haematological malignancy, arises from the abnormal proliferation of immunoglobulin-secreting clonal malignant plasma cells (PCs).[1,2] Genomic studies have demonstrated the genetic complexity of this cancer, which is characterized by marked clonal heterogeneity.[3]
Gene expression profiling of lymphomas from the Emu-myc transgenic mice identified FAM46C among the genes included in the B lymphocyte developmental signature[32] using the GSEA platform[33,34] (MSigDB M1487 geneset, Table S6). These results suggested that FAM46C might be involved in PC differentiation, so we first quantified FAM46C mRNA levels by Quantitative real-time polymerase chain reaction (qRT-PCR) in four BC populations, immature, naïve, memory B cells and PCs isolated from bone marrow (BM) samples obtained from healthy donors.[35]
FAM46C, which is frequently mutated in MM, has recently been described as a new non-canonical poly(A) polymerase (ncPAP).[14,19]
Summary
Multiple myeloma (MM), the second most common haematological malignancy, arises from the abnormal proliferation of immunoglobulin-secreting clonal malignant plasma cells (PCs).[1,2] Genomic studies have demonstrated the genetic complexity of this cancer, which is characterized by marked clonal heterogeneity.[3]. The characterization of FAM46C KO clones revealed that the loss of FAM46C deregulated some migration-related factors and sharply increased the migratory ability of MM cells. These findings could explain the relationship between the presence of FAM46C mutations/deletions in patients with MM and the progression/poor prognosis of the disease. We revealed that both immunoglobulin light and heavy chain mRNAs are direct substrates of FAM46C. This finding demonstrates that the loss of polyadenylation activity is the mechanism by which antibody production is decreased in FAM46C KO clones
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