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Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia
Simeoni, Fabrizio Romero-Camarero, Isabel Camera, Francesco Amaral, Fabio Sinclair, Oliver J Papachristou, E. K. Spencer, Gary J Lie-A-Ling, Michael Lacaud, Georges Wiseman, Daniel H
Simeoni, Fabrizio
Romero-Camarero, Isabel
Camera, Francesco
Amaral, Fabio
Sinclair, Oliver J
Papachristou, E. K.
Spencer, Gary J
Lie-A-Ling, Michael
Lacaud, Georges
Wiseman, Daniel H
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Abstract
Despite absent expression in normal hematopoiesis, the Forkhead factor FOXC1, a critical mesenchymal differentiation regulator, is highly expressed in ?30% of HOXAhigh acute myeloid leukemia (AML) cases to confer blocked monocyte/macrophage differentiation. Through integrated proteomics and bioinformatics, we find that FOXC1 and RUNX1 interact through Forkhead and Runt domains, respectively, and co-occupy primed and active enhancers distributed close to differentiation genes. FOXC1 stabilizes association of RUNX1, HDAC1, and Groucho repressor TLE3 to limit enhancer activity: FOXC1 knockdown induces loss of repressor proteins, gain of CEBPA binding, enhancer acetylation, and upregulation of nearby genes, including KLF2. Furthermore, it triggers genome-wide redistribution of RUNX1, TLE3, and HDAC1 from enhancers to promoters, leading to repression of self-renewal genes, including MYC and MYB. Our studies highlight RUNX1 and CEBPA transcription factor swapping as a feature of leukemia cell differentiation and reveal that FOXC1 prevents this by stabilizing enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex to oncogenic effect.
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2021
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Simeoni F, Romero-Camarero I, Camera F, Amaral FMR, Sinclair OJ, Papachristou EK, et al. Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia. Vol. 36, Cell Reports. Elsevier BV; 2021. p. 109725.