Cpsf1 Regulates Aml1-Eto Fusion Gene Polyadenylation And Stability In T(8;21) Acute Myelogenous Leukemia

Alternative polyadenylation (APA) can alter the three prime untranslated region (3'UTR) length of mRNA transcripts, a crucial region for regulating mRNA metabolism and gene expression. Despite the prevalence and reported importance of APA post-transcriptional regulation in cancer, changes in 3'UTR usage by APA and its contribution to leukemia development have not been thoroughly studied. In acute myelogenous leukemia (AML), t(8;21) is the most common chromosomal abnormality and encodes the AML1-ETO (AE) fusion gene, which dominantly blocks hematopoietic cell differentiation. Previous studies reported that a small amount of non-leukemic t(8;21)+ hematopoietic stem cells (HSCs) never disappeared in long-term remission bone marrows after chemotherapy. These t(8;21)+ HSCs expressed low AE mRNA compared to diagnostic AML cells and possessed normal differentiation into myeloid cells. Another study also reported that a fraction of pediatric t(8;21) AML patients had AE+ clones in their neonatal Guthrie blood spots samples. These data suggest that acquisition of AE is not sufficient for t(8;21) AML development, AE+ HSCs could be a reservoir for pre-leukemic clones, and AE up-regulation is essential for leukemic transformation. However, the mechanism of AE up-regulation has not been revealed. Uncovering this mechanism is highly significant for preventing leukemia development and relapse after treatment.