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Title: The epigenetic and transcriptional consequences of aberrant FoxC1 expression in acute myeloid leukaemia
Author: Gilding, Liam Niall
ISNI:       0000 0004 7231 0948
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2018
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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.
Supervisor: Not available Sponsor: Bloodwise Gordon Piller Studentship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH426 Genetics ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)