Human acute myeloid leukaemias (AMLs) are heterogeneous with respect to the function of the cells that make up the disease. A minority of the cells are leukaemia stem cells (LSCs) which have the ability to self-renew for an extended, if not indefinite, period, thus maintaining and expanding the disease. In order to cure a patient these cells must be eliminated completely, because if they are not, they have the ability to regenerate the disease and induce relapse.
Understanding the cellular mechanisms that regulate the self-renewal of the LSC compartment represents a critical current problem in leukaemia biology. The Leukaemia Biology Group focuses its research on understanding the biology of disordered LSCs in comparison with normal haematopoietic stem cells (HSCs) in a range of distinct categories of haematological malignancy, in order to identify new genes and cellular pathways that are critical for LSC function and which could be targeted by novel therapies. A particular area of interest is the burgeoning field of epigenetics. The group has recently discovered a new candidate therapeutic target in the mixed lineage leukaemia subtype of AML, called LSD1, which is a histone demethylase, and has synthesised novel compounds that inhibit the enzyme and induce differentiation of LSCs in collaboration with the Drug Discovery Unit at the CRUK Manchester Institute.
Figure: Therapeutic targeting of LSD1. (Top) Structure of LSD1 showing SWIRM domain (orange), amine oxidase domain (green) and tower domain (blue). LSD1 demethylates histone H3K4 and H3K9 Me1 & Me2, as well as non-histone targets such as TP53 and DNMT1. (Middle) Mouse leukaemia cells were infected Lsd1 knockdown lentiviruses, or a non-targeting control vector. Image shows typical control AML colonies (containing predominantly myeloblasts) and Lsd1 KD colonies (containing predominantly terminally differentiated macrophages), enumerated after six days of culture. (Bottom) Structure of trans-N-((2-methoxypyridin-3-yl)methyl)-2-phenylcyclopropan-1-amine, termed Compound B in Harris et al., 2012, Cancer Cell.