RNA profiling of BCLAF1 knock-down MOLM-13 cell line

Acute myeloid leukemia (AML) is driven by a combination of genetic alterations and non-mutational mechanisms that disrupt normal hematopoiesis and support leukemic cell survival. While the mutational landscape of AML is well characterized, the non-genetic processes that sustain leukemic maintenance remain comparatively less understood. Using murine models of AML and human AML cell lines, we identify BCL2-associated transcription factor 1 (BCLAF1) as a critical 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 amino acid metabolic target genes essential for leukemic cell survival. Consistently, depletion of BCLAF1 sensitizes AML cells to venetoclax, which is known to disrupt amino acid uptake and metabolism in leukemia cells. 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.