Laising Yen, Ph.D.
Associate Professor
Department of Pathology and Immunology
Baylor College of Medicine

Abstract
One of the hallmarks of cancer is the formation of oncogenic fusion genes as a result of chromosomal translocations. Fusion genes are presumed to occur prior to fusion RNA expression. However, studies have reported the presence of fusion RNAs (such as the BCR-ABL RNA in leukemia) in individuals who were negative for chromosomal translocations. The observation, that fusion RNA could be present prior to fusion gene, raises the possibility that cellular fusion RNA created by trans-splicing could act as a guide RNA to mediate genomic rearrangement by annealing to regions of both chromosomes. A precedent for this mechanism is found in lower organisms such as ciliates. However, RNA-driven genomic rearrangement has not been demonstrated in human cells. Here we provide evidence that expression of a chimeric RNA drives formation of a specified gene fusion via genomic rearrangement in mammalian cells. The process is (1) specified by the sequence of chimeric RNA involved, (2) facilitated by physiological hormone levels, (3) permissible regardless of intra-chromosomal or inter-chromosomal fusion, and (4) can occur in normal cells prior to malignant transformation. Furthermore, we identified an endogenous RNA that acts as the ‘initiator’ RNA to induce TMPRSS2-ERG fusion. The proposed RNA-driven model may provide a mechanism that can ‘specify’ gene fusion partners in early disease stages, and could have fundamental implications in the biology of mammalian genome stability, as well as gene editing technology via mechanisms native to mammalian cells.