GSE125723
CPSF1 regulates expression of leukemogenic fusion genes through modulating alternative polyadenylation
Leukemic fusion genes play a pivotal role in acute myeloid leukemia (AML) pathogenesis. Although previous studies in patients and mice indicated that not only acquisition but also upregulation of leukemic fusion genes is a critical step of AML development, the mechanism of this upregulation is not fully understood. We herein report that 3' untranslated region (3'UTR) shortening through alternative polyadenylation (APA) contributes to the upregulation of leukemic fusion genes. The AML1-ETO leukemic fusion gene in human t(8;21) AML cells uses mainly two polyadenylation signals (PASs). AML1-ETO with the shorter 3'UTR is more stable and the predominant isoform. Furthermore, AML1-ETO 3'UTR length is negatively correlated to mRNA expression in AML blasts and co-existing AML1-ETO+ differentiated cells purified from t(8;21) AML patients. Like AML1-ETO, the MLL-AF9 leukemic fusion gene in human t(9;11) AML cells also uses two PASs and the shorter 3'UTR variant is the predominant isoform in AML cells. We also identified that CPSF1, which is highly expressed in various AMLs, is the main contributor for the 3'UTR shortening of these leukemic fusion genes. CPSF1 knockdown lengthened the 3'UTR of both AML1-ETO and MLL-AF9 mRNAs, decreased fusion gene expression, and suppressed cell proliferation. These findings reveal an important role of CPSF1 in regulating APA of leukemic fusion genes and highlight a previously unknown insight that 3'UTR shortening of leukemic fusion genes could be involved in acute myeloid leukemogenesis. Overall design: mRNA profiles of t(8;21) AML cell lines (Kasumi-1 and SKNO-1 cells), control shRNA-treated Kasumi-1 cells and CPSF1 shRNA-treated Kasumi-1 cells were generated by deep-sequencing.