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Here, we examined the changes in the landscape of transcription start sites 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 B cells from E\u00b5-Tcl1 transgenic mice, which are particularly enriched with intra-genic promoters that generate N-terminally truncated or modified proteins. Intra-genic promoter activation is mediated by (1) loss of function of \u2018closed chromatin\u2019 epigenetic regulators due to the generation of inactive N-terminally modified isoforms or reduced expression; (2) upregulation of transcription factors, including\n                    <jats:italic>c-Myc<\/jats:italic>\n                    , targeting the intra-genic promoters and their associated enhancers. Exogenous expression of\n                    <jats:italic>Tcl1<\/jats:italic>\n                    in MEFs is sufficient to induce intra-genic promoters of epigenetic regulators and promote\n                    <jats:italic>c-Myc<\/jats:italic>\n                    expression. We further found a dramatic translation downregulation of transcripts bearing CNY cap-proximal trinucleotides, reminiscent of cells undergoing metabolic stress. These findings uncovered the role of\n                    <jats:italic>Tcl1<\/jats:italic>\n                    oncogenic function in altering promoter usage and mRNA translation in leukemogenesis.\n                  <\/jats:p>","DOI":"10.7554\/elife.77714","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T06:15:20Z","timestamp":1658297720000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.77714","source":"Crossref","is-referenced-by-count":0,"title":["Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed multiple N-terminally altered epigenetic regulators and a translation stress signature"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9411-3537","authenticated-orcid":true,"given":"Ariel","family":"Ogran","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, The Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Havkin-Solomon","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, The Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirly","family":"Becker-Herman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, The Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keren","family":"David","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, The Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idit","family":"Shachar","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, The Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6251-4723","authenticated-orcid":true,"given":"Rivka","family":"Dikstein","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, The Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2022,8,8]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1016\/j.jmb.2019.04.045","article-title":"refTSS: a reference data set for human and mouse transcription start sites","volume":"431","author":"Abugessaisa","year":"2019","journal-title":"Journal of Molecular Biology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/nature12787","article-title":"An atlas of active enhancers across human cell types and tissues","volume":"507","author":"Andersson","year":"2014","journal-title":"Nature"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41576-019-0173-8","article-title":"Determinants of enhancer and promoter activities of regulatory elements","volume":"21","author":"Andersson","year":"2020","journal-title":"Nature Reviews. 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