The Fusion of and Arises from a -Splicing Event in Normal and Transformed Human Cells

Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic structure and biological roles of , a novel chimeric transcript produced by the fusion of the cell surface receptor and the host gene (), first identified in chronic myeloid leukemia (CML) patients. Surprisingly, we observed that is not just expressed in CML, but also in a variety of normal tissues and cell lines. expression is elevated in pro-monocytic cells resistant to chemotherapy and during monocyte-to-macrophage differentiation. We observed that is a product of -splicing rather than a chromosomal rearrangement and that transcriptional activation of with the CRISPR/Cas9 Synergistic Activation Mediator (SAM) system increases expression. translates into a chimeric protein, which largely resembles CLEC12A but harbours an altered C-type lectin domain altering key disulphide bonds. These alterations result in differences in post-translational modifications, cellular localization, and protein-protein interactions. Taken together, our observations support a possible involvement of in the regulation of function. Our workflow also serves as a template to study other uncharacterized chimeric RNAs.