BCLAF1 controls ATF4 splicing in AML cell lines and mice; its loss sensitizes cells to venetoclax

Researchers report in Science Advances that BCL2-associated transcription factor 1 (BCLAF1) regulates the progression of acute myeloid leukemia (AML) through control of mRNA processing. The work used human AML cell lines and murine AML models. science.orgScience Advancesscience.orgOpen source ↗ The authors note that the mutational landscape of AML is well characterized, while the non-genetic processes that sustain leukemic maintenance are less understood.

Splicing and ATF4

BCLAF1 physically associates with core spliceosome components and regulates alternative splicing, with a predominant effect on intron retention. According to the authors, BCLAF1 is required for the productive splicing of activating transcription factor 4 (ATF4) mRNA, which sustains ATF4 protein expression.

Metabolism and venetoclax

Loss of BCLAF1 reduced ATF4 protein levels, led to downregulation of metabolic target genes and disrupted de novo amino acid biosynthesis. Depletion of BCLAF1 also sensitized AML cells to venetoclax, a clinically used BCL-2 inhibitor.

The authors describe this as a previously unrecognized role of BCLAF1 in coordinating mRNA splicing and metabolic adaptation in AML, and point to its potential as a therapeutic target. They place the finding at the intersection of two cancer hallmarks, aberrant RNA splicing and metabolic reprogramming, whose mechanistic link has remained unclear. The data were obtained in cell lines and in mice.