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FAM46C  is one of the most frequently mutated genes in multiple myeloma. 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 multiple myeloma 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 multiple myeloma 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.

The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma