: A protein-coding circular RNA that regulates DNA damage response in -positive leukemias.

Circular RNAs are a novel class of RNA transcripts, which regulate important cellular functions in health and disease. Herein, we report on the functional relevance of the transcript in acute leukemias. In screening experiments, we found that depletion strongly inhibited the proliferative capacity of leukemic cells with translocations. Mass cytometry experiments identified the aberrant activation of the DNA damage response as an early downstream event of depletion. In experiments, targeting prolonged the survival of mice engrafted with leukemic blasts harboring the Philadelphia chromosome. Mechanistically, we found that was enriched in the cytoplasm and associated with the ribosomes of the leukemic cells. We detected a cryptic open reading frame within the sequence and found that could generate a peptide product. The 1-derived peptide interacted with proteins of the BTR complex and enhanced BTR complex formation, thereby increasing tolerance to genotoxic stress.