Biology subjects

Altea-Manzano, P.

Publications and source records attributed to Altea-Manzano, P..

3 recordsLinked to original sources

bioRxiv2026

BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia

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 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 de novo 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. Statement of significanceAberrant 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.

cancer biology↗

bioRxiv2022

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation

Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-{kappa}B subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-{kappa}B signaling.

cancer biology↗

bioRxiv2022

In vivo CRISPR screen defines Slc25a37 as an organ-specific regulator of antioxidant metabolism in metastasis

Withdrawal StatementThe authors have withdrawn their manuscript owing to the detection of inaccurate data analysis in some figure panels that leads in some but not all cases to a different interpretation of the data after corrected analysis. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

cancer biology↗