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EYA1/SIX1/HOXA9 form a trimeric complex that sustains acute myeloid leukaemia

ABSTRACT: Acute Myeloid Leukaemia (AML) is a highly heterogeneous disease characterised by an abnormal transcriptional landscape that results in a block in normal blood cell differentiation and aberrant self-renewal. Dysregulation of Homeobox A9 (HOXA9) expression is a hallmark of multiple AML subsets. Although HOXA9 is critical for maintaining leukaemic transformation, it has proven to be a challenging druggable target, and the underpinning molecular mechanisms through which it promotes leukaemogenesis remain elusive. Here, we report the existence of a tripartite complex between eyes absent 1 (EYA1), sine oculis homeobox 1 (SIX1) and HOXA9 in monocytic zinc finger (MOZ) and mixed-lineage leukaemia (MLL) rearranged AMLs. We employed ChIP-seq, together with RNA-seq, to identify regions bound and transcriptionally upregulated in a MOZ-TIF2 driven model of AML. Using RNA-seq, we demonstrated that EYA1 potentiates the transforming capacity of HOXA9 to confer a greater level of differentiation block via upregulation of Wnt and epithelial to mesenchymal transition (EMT) signalling cascades and suppression of myelo-monocytic programmes. We next sought to define the impact of pharmacologically destabilising the EYA1/SIX1/HOXA9 complex using Benzarone. Through a single cell RNA-Seq timecourse following treatment of MOZ-TIF2 cells with Benzarone, we provide evidence that disruption of EYA1 and its interactions results in differentiation of these cells. To prove the specificity of Benzarone towards EYA1, we also conducted RNA-Seq on cells expressing EYA1 and HOXA9 or HOXA9 alone.

ORGANISM(S): Mus musculus

PROVIDER: GSE154447 | GEO | 2024/07/01

REPOSITORIES: GEO

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EYA1/SIX1/HOXA9 form a trimeric complex that sustains acute myeloid leukaemia

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