Identification, characterisation and therapeutic targeting of leukaemic stem/propagating cells in Acute Myeloid Leukaemia

There are ~3000 new cases a year in the UK of Acute Myeloid Leukaemia (AML). This is the most common aggressive leukaemia. Despite advances in treating patients under the age of 60 years, 50% of these patients still die of their disease. Furthermore, 80% of patients are over the age of 60 and in this age group only 5% of patients are cured. Thus, we need to improve therapy. AML mainly arises sporadically through acquisition of genetic changes in DNA in multiple genes that regulate the complex process of blood cell production. In some patients there is a preleukaemia condition called Myelodysplasia (MDS). One way to further our understanding AML is to define the compendium of genetic changes throughout all our DNA in both AML and MDS and assess how changes deregulate normal blood stem and progenitor cells and transform them into cancerous populations. This necessary information provides a rational platform for future developments to directly benefit patient care. Furthermore study of MDS and AML provides a model to discover general principles in cancer biology and therapy.

Our aim is to characterise the heterogeneous populations of leukaemia propagating cells (LPC) in adult and childhood Acute Myeloid Leukaemia (AML) at functional, genetic, epigenetic and molecular levels, eventually at a single cell level, to improve our basic understanding of leukaemia initiation and propagation. The ultimate aim is to translate this knowledge to improve survival rates in patients. Recent studies from our laboratory and other laboratories have shown that, within any one patient’s tumour, there is functional, molecular and genetic heterogeneity of tumour propagating populations. Though not yet formally demonstrated, layered upon this will likely be epigenetic heterogeneity. Thus, our key questions centre around understanding: a) the nature of this heterogeneity; b) how it arises and c) how different aspects of heterogeneity impact on each other. From a tumour biology perspective, a central hypothesis we will work towards testing is that there are specific molecular attributes present in AML LPC, but absent in downstream progeny, that explain LPC’s ability to propagate tumours whereas downstream progeny cannot. Experimentally, these studies will initially be cell population based. We will purify distinct immunophenotypic primary human AML populations, test their in vivo function, and determine their molecular, genetic and epigenetic profiles. This will be an iterative process. But, ultimately, these studies will have to be conducted at the single cell level,. To begin with, we will overlay single cell molecular and genetic analysis on the cell population-based studies. From a translational standpoint, our key hypotheses are: A) AML LPC are the chemoresistant relapse-driving populations. B) LPC can be therapeutically targeted. Only if both hypotheses are proven correct will be able to improve survival for patients. To test the first hypothesis, we will track LPC from diagnosis through therapy. To address the second hypothesis, we will continue work with Stanford to develop a combination of therapeutic antibodies targeting LPC antigens. Once again, there are huge challenges here, that include: a) defining a window between efficacy and toxicity given that many LPC markers are widely expressed b) defining cocktails of antibodies that target all chemoresistant LPCs.