Identifying the DNA binding specificity of chromatin complexes in leukaemia

Leukaemia is a group of blood cell cancers.

In a particularly aggressive form of this cancer, infant acute lymphoblastic leukaemia (ALL) a frequent genetic aberration involves the rearrangement of the chromosome at the site of the Mixed Lineage Leukaemia gene (MLL) resulting in fusion with other chromosomes to generate MLL fusion proteins of which the most common is AF4.

In multi-cellular organisms the DNA strand is wound around histone proteins which can be altered by the addition or removal of methyl groups by chromatin modifiers such as MLL. These methyl marks are frequently associated with the regulation of gene expression.

MLL has been observed to bind at further regions of DNA away from genes also involved in the regulation of gene expression known as enhancers. However, it is unclear how MLL binds to these regions.

During my PhD, I will use several different lines of enquiry to understand how MLL, the MLL-AF4 fusion protein and proteins known to associate with MLL such as Menin bind to enhancers and if they have preference for specific DNA sequences.

This work will help us to understand how altered of gene expression in ALL is controlled by MLL in order to drive leukaemia.