Ribosomal Protein Rpl22 Regulates Development and Transformation Via Altering RNA Processing

Although it has long been reported that mutations in ribosome proteins (RP) are associated with increased cancer risk in humans, the molecular basis why which RP mutations do so remains unclear. Nevertheless, the prevailing view is that RP mutations, such as Rps19, are thought to alter transformation potential through general impairment of ribosome biogenesis or function. Importantly, recent observations are beginning to challenge this notion as too simplistic. We have determined that the RP, Rpl22, is not essential for ribosome biogenesis or global protein synthesis; however, its inactivation impairs the development of normal T lymphocytes and increases their transformation potential. Indeed, RPL22 is inactivated in human T acute lymphoblastic leukemia (T-ALL) and this is associated with reduced survival. Moreover, Rpl22-deficiency accelerates development of leukemia in a myristylated Akt2 transgenic (MyrAkt2 Tg) mouse model of T-ALL. To gain insight into how Rpl22 inactivation facilitates development of leukemia, we are performing unbiased transcriptomic and proteomic analysis on Rpl22+/+ and Rpl22-/- thymic lymphomas arising in the MyrAkt2 Tg model, and in an Rpl22-/- lymphoma reconstituted with Rpl22. Interestingly, relatively few changes in mRNA transcript read depth were observed; however, substantial differences in the proteome were observed. Pathway analysis revealed that the loss of Rpl22 altered the expression of proteins regulating RNA-processing, in particular RNA-splicing. Interestingly, interrogation of the transrciptome data for alternative splicing revealed that alterations in exon usage. The ability of Rpl22 to influence splicing appears to be conserved across species as alternative splicing was also observed in zebrafish embryos in which Rpl22 was knocked down using morpholino oligonucleotides. Consequently, we hypothesize that Rpl22 regulates biological events through its ability of binding to RNA targets, and controlling the expression of their protein products at least in part through altering mRNA splicing. How Rpl22 changes mRNA splicing pattern is currently under investigation.