BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia
8 affiliations
- 1Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain.
- 2Departamento de Genética, Universidad de Sevilla, 41012 Seville, Spain.
- 3Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
- 4Department of Molecular Biotechnology and Health sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
- 5Center for Human Technologies, Istituto Italiano di Tecnologia (IIT), Genova, Italy.
- 6Departamento de Biología Celular, Universidad de Sevilla, 41012 Seville, Spain.
- 7Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
- 8Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Abstract
Acute myeloid leukemia (AML) is driven by 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 sustaining leukemic maintenance remain less understood. Using human AML cells and murine models, 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 programs in leukemic cells. Mechanistically, BCLAF1 is required for productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein levels and downstream metabolic gene expression programs. Loss of BCLAF1 reduces ATF4 levels, leading to impaired de novo amino acid biosynthesis and increased sensitivity to venetoclax. Together, these findings uncover a previously unrecognized mechanism linking RNA splicing control to metabolic adaptation in AML, identifying BCLAF1 as a potential therapeutic vulnerability.
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BibTeX
@article{lopezhernandez2026bclaf1,
title = {{BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia}},
author = {Laura López-Hernández and Stephanie J. Crowley and Sara Cea-Sánchez and Ricardo de Arellano and Neetij Krishnan and Patrick Toolan-Kerr and Lynn White and Domenico Ignoti and Emily Soto-Hidalgo and Stefano Gustincich and Román González-Prieto and Luca Pandolfini and Isaia Barbieri and Patricia Altea-Manzano and Jeffrey A. Magee and Francesca Ferraro and Samuel J. Taylor and Jeffrey J. Bednarski and Gonzalo Millán-Zambrano},
journal = {Science Advances},
year = {2026},
month = nov,
doi = {10.1126/sciadv.aeg0571},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aeg0571},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia
AU - Laura López-Hernández
AU - Stephanie J. Crowley
AU - Sara Cea-Sánchez
AU - Ricardo de Arellano
AU - Neetij Krishnan
AU - Patrick Toolan-Kerr
AU - Lynn White
AU - Domenico Ignoti
AU - Emily Soto-Hidalgo
AU - Stefano Gustincich
AU - Román González-Prieto
AU - Luca Pandolfini
AU - Isaia Barbieri
AU - Patricia Altea-Manzano
AU - Jeffrey A. Magee
AU - Francesca Ferraro
AU - Samuel J. Taylor
AU - Jeffrey J. Bednarski
AU - Gonzalo Millán-Zambrano
PY - 2026
DA - 2026/11/04
JO - Science Advances
DO - 10.1126/sciadv.aeg0571
UR - https://www.science.org/doi/abs/10.1126/sciadv.aeg0571
AB - Acute myeloid leukemia (AML) is driven by 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 sustaining leukemic maintenance remain less understood. Using human AML cells and murine models, 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 programs in leukemic cells. Mechanistically, BCLAF1 is required for productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein levels and downstream metabolic gene expression programs. Loss of BCLAF1 reduces ATF4 levels, leading to impaired de novo amino acid biosynthesis and increased sensitivity to venetoclax. Together, these findings uncover a previously unrecognized mechanism linking RNA splicing control to metabolic adaptation in AML, identifying BCLAF1 as a potential therapeutic vulnerability.
SN - 2375-2548
ER -