Dysregulation of SHFM1, a Novel Target for Prevention of Genomic Instability in Myeloma, Is Associated with Epigenetic Changes at Specific CpG Sites

We have previously demonstrated that elevated homologous recombination (HR) activity mediates genomic instability and progression in myeloma. We, therefore, hypothesized that mechanisms underlying dysregulation of HR, drive genomic instability and have potential to serve as novel markers of progression and target to make cancer cells static. In an attempt to identify molecular intermediates underlying increased HR, we conducted a high-throughput shRNA screen using HR activity in MM cells as an endpoint, and identified split hand/split foot malformation locus 1 - SHFM1 - as a novel regulator of HR in myeloma. We demonstrate that suppression of SHFM1 using specific lentiviral shRNA knockdown inhibits HR activity in myeloma as well as other (esophageal) cancer cells. Suppression of HR activity is also associated with reduction in spontaneous DNA breaks thus having a positive impact on genomic integrity. We have also observed that suppression of SHFM1 gene lead to reduction in acquisition of new genomic changes by both copy number alteration as well as SNPs. Evaluation of expression profile in 330 MM patients and 18 normal plasma cells indicated that the gene is overexpressed in myeloma, relative to normal plasma cells (P = 0.0059). Expression of this gene in myeloma also significantly correlates with its copy number (R=0.43; P In summary our results highlight SHFM1 as an important gene modulating genomic instability and its control by methylation provides an insight into epigenomic control of DNA stability. Disclosures No relevant conflicts of interest to declare.