Role of alternative polyadenylation dynamics in acute myeloid leukaemia at single-cell resolution

Alternative polyadenylation (APA) has been discovered to play regulatory roles in the development of many cancer cells through preferential addition of a poly(A) tail at specific sites of pre-mRNA. A recent study found that APA was involved in the mediation of acute myeloid leukaemia (AML). However, unlike gene expression heterogeneity, little attention has been directed toward variations in single-cell APA for different cell types during AML development. Here, we used single-cell RNA-seq data of a massive population of 16,843 bone marrow mononuclear cells (BMMCs) from healthy and AML patient samples to investigate dynamic APA usage in different cell types. Abnormalities of APA dynamics in the BMMCs from AML patient samples were uncovered compared to the stable APA dynamics in samples from healthy individuals, as well as lower APA diversity between eight cell types in AML patients. Genes with APA dynamics specific to the AML samples were significantly enriched in cellular signal transduction pathways that contribute to AML development. Moreover, many leukaemic cell marker genes such as NF-κB, GATA2 and IAP-Family genes exhibited APA dynamics that specifically affected abnormal proliferation and differentiation of leukemic BMMCs. Additionally, mature erythroid cells displayed greater APA dynamics and global 3' UTR shortening compared with other cell types. Our results revealed extensive involvement of APA regulation in leukemia development and erythropoiesis at the single-cell level, providing a high-resolution atlas to navigate cellular mRNA processing landscapes of differentiated cells in AML.