Misexpression of transcription factors in myeloid leukaemia

This 4 year PhD studentship offered in Professor Tim Somervaille’s group is based at the Manchester Cancer Research Centre [MCRC], South Manchester

Acute myeloid leukaemia (AML) is a cancer of the blood and bone marrow defined by a block to the normal differentiation of myeloid cells resulting in accumulation of blasts and failure of normal blood cell formation. Despite the genetic heterogeneity the differentiation block is the cardinal feature of the disease and emerging evidence reveals that mutations cluster in particular categories of gene.

Indeed, the great majority of patients with AML have one or more mutations targeting a transcription factor, chromatin modifier or regulator of DNA methylation and this emphasises the absolute centrality of epigenetic and transcription factor dysfunction to the disease. Investigation of this dysfunction holds rich promise for discovery of new therapeutic targets for development through to the clinic: AML remains a significant cause of morbidity and mortality, with poor long-term survival despite treatments including chemotherapy and bone marrow (BM) transplantation.

An essential point is that we do not fully understand how the recurring genetic mutations in the disease confer the differentiation block. In recent years the Somervaille lab has uncovered new and unexpected transcription factor genes which make a frequent and substantial contribution. FOXC1 and IRX3, which are normally strongly repressed in haematopoiesis, are expressed at high level to functional effect in ~30% and ~40% respectively of the multiple genetic subtypes of AML associated with high HOXA/B gene expression (e.g. NPM1 mutated, MLL-translocated and t(6;9) cases).

Given these and other observations that transcription and epigenetic factor dysfunction is of central importance in AML, understanding how epigenetic dysfunction arises and contributes to the differentiation block holds rich promise for the identification of new therapeutic targets for patient benefit. In addition to killing leukaemia cells with chemotherapy, induction of differentiation is a major goal of treatment.

Through analysis of the AML chromatin landscape this project will make use of leading edge technologies and experimental approaches to discover how transcription factor genes FOXC1 and IRX3 are derepressed in AML to confer a differentiation block.

Key recent manuscripts that serve as a platform for the proposed project include:

TDD Somerville et al. Frequent derepression of the mesenchymal transcription factor gene FOXC1 in acute myeloid leukaemia. Cancer Cell 14:329-342.

TDD Somerville et al. Derepression of the Iroquois homeodomain transcription factor IRX3 confers differentiation block in acute leukemia. Cell Reports 22:638-652.

Closing date: Monday 3 December 2018 – 17:00 hrs GMT.

Interview date: Monday 14 January 2019, Alderley Park, Cheshire.