A differentiation block is the cardinal pathologic feature of acute myeloid leukemia (AML) but the underlying mechanisms are incompletely understood. Despite absent expression in normal hematopoietic lineages, the Forkhead family transcription factor FOXC1, which is a critical regulator of normal mesenchymal and mesodermal differentiation, is highly expressed in ~20% of cases of AML where it confers a block to monocyte/macrophage lineage differentiation and inferior outcome. Through integrated proteomics and bioinformatics approaches, I have discovered that FOXC1 interacts with RUNX1 through its Forkhead DNA binding domain and that the two factors co-occupy a discrete set of primed and active enhancers distributed close to monocyte/macrophage differentiation genes. FOXC1 stabilises association of RUNX1, HDAC1 and the Groucho family repressor protein TLE3 at these sites to limit enhancer activity: FOXC1 knockdown induced loss of repressor proteins, gain of CEBPA binding, enhancer acetylation and upregulation of nearby genes, including KLF2. Furthermore, it triggered genome-wide redistribution of RUNX1, TLE3 and HDAC1 from enhancers to promoters leading to repression of self-renewal genes including MYC and MYB. My studies highlight RUNX1 and CEBPA transcription factor swapping at enhancers and promoters as a key feature of leukemia cell differentiation, and reveal that FOXC1 prevents this by stabilising enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex, to oncogenic effect.
Date of Award | 31 Aug 2021 |
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Original language | English |
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Awarding Institution | - The University of Manchester
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Supervisor | Tim Somervaille (Supervisor) & Esther Baena Chaparro (Supervisor) |
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The Role Of The Forkhead Transcription Factor FOXC1 In Acute Myeloid Leukaemia
Simeoni, F. (Author). 31 Aug 2021
Student thesis: Phd