Abstract
SummaryDespite 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.
Highlights
Acute myeloid leukemia (AML) is a blood cancer characterized by a block to normal myeloid lineage differentiation
Few AML-associated genetic lesions are exclusively found in AML, and even those such as FLT3 internal tandem duplications or NPM1 mutations, which are rarely found in clinical contexts other than AML, yield prominent myeloproliferative phenotypes when modeled in mice (Kelly et al, 2002; Vassiliou et al, 2011)
To confirm that FOXC1 contributes to the differentiation block exhibited by Fujioka cells, we performed FOXC1 knockdown (KD) and observed differentiation, as evidenced by morphology, increased expression of the monocyte/macrophage lineage differentiation marker CD86, reduced clonogenic activity, a reduced proportion of cells in the SG2M phase of the cell cycle, as well as an increase in apoptosis (Figures 1A–1D and S1C– S1E)
Summary
Acute myeloid leukemia (AML) is a blood cancer characterized by a block to normal myeloid lineage differentiation. The range of balanced translocations, point mutations, and indels associated with this malignancy is largely characterized, the mechanisms by which these genetic lesions confer a differentiation block is less well understood This is emphasized by studies that show that many AML-associated mutations, including some chromosomal abnormalities, may be found in chemotherapy-treated patients in complete remission, in patients with myelodysplasia prior to evolution to AML, or in aging individuals with normal blood counts (i.e., clonal hematopoiesis of indeterminate potential) (Wiseman et al, 2016; Sperling et al, 2017; Jongen-Lavrencic et al, 2018; Jaiswal and Ebert, 2019). In addition to killing leukemia cells with chemotherapy, induction of differentiation is a major goal of treatment
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