1. Mechanistic insights into aberrant transcriptional programming in acute myeloid Leukaemia. Bloodwise programme grant (with Peter Cockerill)
Postdocs: Anetta Ptasinska, Salam Assi, Paulynn Chin, Dan Coleman. PhD students: Assunta Adamo and Sandeep Potluri (Clinical Fellow).
Collaborators: Olaf Heidenreich, University of Newcastle, JJ Schuringa, University of Groningen, Dan Tenen, Harvard Stem Cell Institute and National University of Singapore, Manoj Raghavan, Haematology, Birmingham.
In this program, we examine the molecular mechanisms underlying how normal and aberrant leukaemic transcription factors interact with the epigenetic regulatory machinery, reprogram the epigenetic landscape of normal human precursor cells and initiate the vast deregulation phenomena that we observe in malignant cells. We are also developing methods and computational tools that will allow us to model how the human epigenome swings back to normal, once we eliminate specific leukaemia-initiating oncogenes and/or block aberrant signalling through therapy.
2. Finding therapeutic targets in FLT3-ITD AML using a systems biology approach. MRC project grant (with P.Cockerill and Olaf Heidenreich / Helen Blair, Newcastle)
Postdocs: Dan Coleman, Peter Keane
Collaborators: John Bushweller, University of Virginia and Manoj Raghavan, Haematology, Birmingham.
Acute myeloid leukemia (AML) is an aggressive haematological malignancy which is caused by mutations interfering with hematopoietic differentiation (class II) followed by mutations conveying a proliferative advantage (class I). Activating mutations of FMS-like Tyrosine Kinase 3 (FLT3-receptor) are the most common class I mutations and occur in 30% of de novo AML. The prognosis of FLT3-ITD AML is extremely poor and new drugs and combination therapies are therefore urgently needed. Importantly, we need to obtain systems-level information on the targets affected by drugs and mechanistic information on how drugs work. It is now clear that the FLT3-ITD mutation does not just promote growth, but also has a profound influence on the transcriptional and epigenetic landscape. Our recent publications uncovered a common set of FLT3-ITD specific deregulated genes, identified the core deregulated transcriptional network of this type of AML and determined FLT3-ITD-specific deregulated pathways. In this project we build on this work to define the role of such genes and pathways with respect to the maintenance of FLT3-ITD AML development and maintenance as well as the development of drug resistance.
3. Understanding the interplay of enhancers, chromatin priming elements and signals regulating dynamic gene expression in development. BBSRC project grant (with JB Cazier and James Bentley Brown, Centre for Computational Biology).
Postdocs: Benjamin Edgington White, Wakil Sarfaraz. PhD student: Alexander Maytun.
In this project we are using the in vitro differentiation of embryonic stem cells into blood cells to ask the question of how genes are activated in development and which role outside signals play in this process. We are using these data to generate mathematical models that would allow us to predict the activity of different types of cis-regulatory elements at specific stages of development.
4. System-wide analysis of transcriptional and chromatin reprogramming by EVI1 and RUNX1-EVI1 oncoproteins. Kay Kendall Leukaemia Fund.
Postdoc: Sophie Kellaway
The transcription factor RUNX1 is crucial for the establishment of haemopoiesis and mutation of this gene plays an important role in myeloid leukemia. However, little is known about the mechanistic details of how mutant versions of RUNX1 subvert normal haemopoietic development and counteract normal RUNX1 activity. Using the differentiation of mouse embryonic stem (ES) cells as model we address this question.
5. Modelling acute myeloid leukaemia in human ES cell derived haematopoietic precursor cells. U21 Melbourne studentship
PhD student: Monica Nafria I Fedi
Co-applicants: Andrew Elefantly, University of Melbourne
Genetic changes in cancer cells disturb the finely tuned balance of the interaction of the transcription regulatory machinery with the genome. However, tumour development does not occur in one step. After the first mutation, cells accumulate additional mutations and undergo extensive selection which completely alters their transcriptional network. For haematopoietic malignancies such as acute myeloid leukaemia (AML), we know therefore very little about how the first genetic change that occurs in stem/early precursor cells alters the epigenetic landscape. To address this question, the Bonifer lab and the Elefanty lab in Melbourne who is a world leader in blood cell differentiation from human embryonic stem (hESCs) cells have collaborated and established genetically engineered hESC lines carrying inducible versions of leukaemic oncogenes and learned how to differentiate these cells into blood precursors. We are now using this system to systematically test how the successive expression of leukaemic oncoproteins impact of human haematopoiesis.