Can we be SMaRT-er in our approach to cancer therapy?

Spliceosome-mediated RNA trans-splicing (SMaRT) is a molecular tool that facilitates genetic reprogramming on the RNA level (Wally et al., 2012). SMaRT exploits the cells own splicingmachinery to recombine two RNA molecules: the endogenous RNA target and the RNA trans-splicing molecule (RTM). The end product is a chimeric RNA wherein part of the message encoded by the target RNA is replaced with one provided by the RTM. The specificity of the trans-splicing reaction is conferred by an anti-sense binding domain complementary to a non-coding region within the target RNA. This serves to tether the RTM to its target RNA, bringing donor and acceptor splice sites on both molecules into close proximity thereby allowing the transsplicing reaction to occur. Since its first demonstration in 1999, where it was used in a cancer suicide gene therapy approach (Puttaraju et al., 1999), SMaRT has primarily made a niche in the field of gene therapy where it has successfully been employed in pre-clinical investigations for the therapy of various genetic disorders, including cystic fibrosis, hemophilia A, spinal muscular atrophy, and the severe skin blistering disease epidermolysis bullosa (as reviewed in Wally et al., 2012). In this issue, Uckun et al. take the concept of SMaRT-mediated repair back to its roots and explore its use in the repair of an oncogenic defect, CD22ΔE12, in childhood B-precursor leukemia (BPL), the largest subset of B-lineage acute lymphoblastic leukemia (ALL) (Uckun et al., 2015a). BPL cells express dysfunctional CD22, a principal negative regulator of B cell receptor signaling, due to homozygous intronic mutations. These mutations result in aberrant splicing and loss of exon 12, leading to translation pre-termination and the generation of a truncated protein which lacks the regulatory domains required for proper signal transduction and apoptosis induction (Uckun et al., 2010). Forced expression of human CD22ΔE12 in mice resulted in spontaneous development of B-ALL with a gene signature that closely recapitulates that of human ALL, indicating that CD22ΔE12 is an oncogenic driver (Uckun et al., 2015a, 2010). Because CD22ΔE12 is associated with aggressive and chemo-refractory disease, the authors sought to repair this defect by using SMaRT technology to replace the exons 10–14 of the mutant pre-mRNA with the wildtype sequence using a rationally designed RTM (Uckun et al., 2015b). Transfection of the RTM into leukemiainitiating ALL cells significantly reduced their ability to cause leukemia