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While the mutational landscape of AML is well characterized, the non-genetic processes that sustain leukemic maintenance remain comparatively less understood. Using human AML cell lines and murine models of AML, we identify BCL2-associated transcription factor 1 (BCLAF1) as a key regulator of leukemic progression through control of mRNA processing. BCLAF1 physically associates with core spliceosome components and regulates alternative splicing, with a predominant effect on intron retention. We demonstrate that BCLAF1 is required for the productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein expression. Loss of BCLAF1 reduces ATF4 protein levels, leading to downregulation of metabolic target genes and disruption of\n                  <jats:italic>de novo<\/jats:italic>\n                  amino acid biosynthesis. Furthermore, depletion of BCLAF1 sensitizes AML cells to venetoclax, a clinically relevant BCL-2 inhibitor. Together, these findings uncover a previously unrecognized role for BCLAF1 in coordinating mRNA splicing and metabolic adaptation in AML, highlighting its potential as a therapeutic target.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of significance<\/jats:title>\n                  <jats:p>Aberrant RNA splicing and metabolic reprogramming are hallmarks of cancer, yet how these processes are mechanistically linked remains unclear. This study identifies BCLAF1 as a key regulator connecting splicing control to amino acid metabolism in acute myeloid leukemia, revealing a previously unrecognized functional vulnerability at the intersection of these pathways.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.19.700325","type":"posted-content","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T22:45:13Z","timestamp":1769121913000},"source":"Crossref","is-referenced-by-count":1,"title":["BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia"],"prefix":"10.64898","author":[{"given":"Laura","family":"L\u00f3pez-Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain"},{"name":"Departamento de Gen\u00e9tica, Universidad de Sevilla, 41012 Seville, 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