Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature

The transformation of normal to malignant cells is accompanied by substantial changes in gene expression programs through diverse mechanisms. Here we examined the changes in the landscape of transcription start sites (TSSs) and alternative promoter (AP) usage and their impact on the translatome in TCL1-driven chronic lymphocytic leukemia (CLL). Our findings revealed a marked elevation of APs in CLL cells from Eµ-Tcl1 transgenic mice, which are particularly enriched with intragenic promoters that generate N-terminally truncated or modified proteins. Intragenic promoter activation is mediated by (i) loss of function of ‘closed chromatin’ epigenetic regulators due to the generation of inactive N-terminally modified isoforms or reduced expression; (ii) upregulation of transcription factors, including c-Myc, targeting the intragenic promoters and associated enhancers. Exogenous expression of Tcl1 in MEFs is sufficient to induce intragenic promoters of epigenetic regulators and promote c- Myc expression. We further found a dramatic translation downregulation of transcripts bearing CNY cap-proximal tri-nucleotides, reminiscent of cells undergoing metabolic stress. These findings uncovered the role of Tcl1 oncogenic function in altering promoter usage and mRNA translation in leukemogenesis.