The epigenetic and transcriptional consequences of aberrant FoxC1 expression in acute myeloid leukaemia

Gilding, Liam Niall (2018). The epigenetic and transcriptional consequences of aberrant FoxC1 expression in acute myeloid leukaemia. University of Birmingham. Ph.D.

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Abstract

FOXC1 encodes a mesenchymal transcription factor that is not normally expressed in haematopoietic cells. However, recent studies from this and another laboratory demonstrated that FOXC1 is inappropriately de-repressed in Acute Myeloid Leukaemia (AML). Through epigenomic profiling of primary AML samples, we showed that FOXC1 was specifically upregulated in the aggressive FLT3-ITD subtype of AMLs, in parallel with the activation of FOX:E-box composite cis-regulatory elements. Furthermore, complementary studies from the Somervaille laboratory demonstrated that FoxC1 expression in AML was leukaemogenic by establishment of a monocyte differentiation block and enhancement of clonogenic potential.

Collectively, these data indicated that FoxC1 plays a critical role in leukaemogenesis, but the target genes and mechanisms by which this occurred were not known. To address this, we performed an integrative genome-wide analysis of FoxC1 binding, chromatin accessibility and gene expression in primary AML samples, in vivo models and cell lines. These studies revealed that FoxC1 acts to block normal myeloid differentiation by contributing to the widespread repression of differentiation-specific target genes. Critically, we identify Meis2, a proto-oncogene which collaborates with Hoxa9, as a putative direct target of FoxC1, providing compelling indications of a potential FoxC1-dependent oncogenic mechanism.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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