Epigenetic Control of Gene Expression in Leukaemia and Haematopoiesis

Acute lymphoblastic leukaemia (ALL) in children used to be a disease that was untreatable. Thankfully, general
care for ALL has greatly improved so that ~90% of children are cured. Unfortunately, there are still rare subsets
of ALL that have a tendency to relapse and are untreatable. We are trying to understand the molecular details of
these rare, incurable ALLs in order to design new therapies. In order to do this, we study how epigenetics impacts
gene regulation. Genes are made up DNA, and they reside in the nucleus, where they act as hardware for the
cell that needs to be "read" in order to be functional. When genes are read (or what we call "activated")
inappropriately, this can cause aberrant behaviour such as cancerous growth. Epigenetics is information that is
not stored directly in the DNA itself. For example, some epigenetic information is stored in chemical modifications
carried by histone proteins that interact with DNA in a structure called chromatin. It is becoming clear not only that
aberrant epigenetic changes are common in many human diseases such as leukaemia, but that these changes
by their very nature are reversible. Our goal is to help design therapies that can target these reversible epigenetic
changes.

My overall goal is to discover how epigenetic systems are leveraged in cancer to create pathogenic gene
expression states and to use this basic knowledge to develop new targeted therapies. I focus on high-risk infant
and childhood acute lymphoblastic leukaemias (ALLs), the most common form of paediatric cancer, for which
relapse and refractory disease is largely untreatable. In this group of aggressive cancers, we have recently
discovered that Mixed Lineage Leukaemia rearrangements (MLL-r) cause an altered epigenetic landscape which
may drive the emergence of novel enhancers and pathogenic gene expression states. We currently have no
understanding of how this occurs or contributes to patient prognosis. To address this fundamental question, we
will now exploit our novel CRISPR/Cas9 human fetal derived ALL models to discover whether enhancer
emergence in ALL is dependent on a pre-existing permissive epigenetic state, or is created de novo. I will also
investigate how distinct chromatin proteins drive enhancer function and create the gene expression states that
define prognosis in poor risk ALLs. To translate these discoveries, we have formed a new spinout company,
Sandymount Therapeutics, for which basic discoveries will drive the drug discovery pipeline and support my
bench to bedside aspirations.