Team Leader
What we do
Survival rates are now approaching 90% for children diagnosed with acute lymphoblastic leukaemia (ALL). However, current treatment often results in severe chronic health conditions, and outcomes for children with relapsed ALL remain poor.
Considerable effort has been made to understand the molecular aberrations that underpin the development and progression of ALL, with the ultimate aim of developing novel therapeutic approaches tailored to the unique genetics (mutational signature) of each child’s cancer. Although critical oncogenic mutations have now been identified through large-scale next generation sequencing efforts, many of these have only been studied in isolation, and targeting such mutations using a single therapeutic agent often fails to yield true clinical benefit.
There is a critical need to move away from the current paradigm of ‘one variant, one therapy’. To maximise clinical impact, we need to better understand the functional relationship between multiple co-occurring mutations, so we can design intelligent combination approaches for the treatment of ALL.
As part of our ongoing efforts, we use both cell line and in vivo mouse models together with CRISPR-Cas9, ChIP-seq, ATAC-seq, nanopore-sequencing and RNA-seq base technologies to model how these different mutations cooperate with one another and drive disease. It is hoped that this, in turn, will help us design more targeted therapies.
Research projects
Characterising transcriptome splicing in T-cell acute lymphoblastic leukaemia
Contact: Dr Charley de Bock, CdeBock@ccia.org.au
Transcriptional deregulation is a hallmark of cancer, and is driven not only by the ectopic expression of transcription factors but also by the deregulation of co-factors involved in transcriptome splicing. We have shown using proteomics that mutant JAK3 signalling regulates a number of RNA-binding proteins involved in RNA splicing.
Our aims are to:
(i) characterise the alternatively spliced transcriptome downstream of mutant JAK3 signalling using long read sequencing in combination with short read sequencing in clinically relevant T-ALL samples
(ii) use targeted proteomics and real-time quantitative PCR to confirm the presence and expression of novel isoforms
(iii) assess the in vivo leukaemogenic potential of novel alternative transcript usage within our established mutant JAK3(M511I) T-ALL mouse model.
Single cell lineage tracing analysis in a preclinical model of T-cell acute lymphoblastic leukaemia
Contact: Dr Charley de Bock, CdeBock@ccia.org.au
Disease progression and relapse for the majority of cancers, including leukaemia, is driven by intra-tumoural heterogeneity that results from branching tumour evolution. Indeed, relapsed acute lymphoblastic leukaemia (ALL) is often derived from an ancestral and therapeutically resistant leukaemic clone. Understanding leukaemia evolution should therefore help us to both define the order and constraints of early mutational events that drive disease, and identify genetic dependencies that can be therapeutically targeted.
Epigenetic profiling and eradication of relapse-initiating cells in paediatric acute lymphoblastic leukaemia
Contact: Dr Charley de Bock, CdeBock@ccia.org.au
Glucocorticoids are among the most effective classes of drugs used to treat ALL and are used in all contemporary multi-agent treatment modalities for ALL. However, in a subset of patients a small fraction of ALL cells survive intense drug treatment, resulting in relapse with overall poor outcome. We identified novel epigenetic mechanisms of glucocorticoid resistance and recently established a single-cell profiling platform to map gene transcription and epigenetic marks in drug-resistant ALL cells in the mouse bone marrow after in vivo drug treatment.
In this project we will test the following hypotheses:
- epigenetic modifications in subpopulations of ALL cells in the bone marrow provide a survival advantage during exposure to chemotherapy in vivo resulting in relapse
- reversing these epigenetic aberrations will eradicate drug-resistant ALL cells and prevent relapse.
Determining the molecular role of the FAT1 cadherin in paediatric acute lymphoblastic leukaemia
Contact: Dr Charley de Bock, CdeBock@ccia.org.au
The gene encoding the FAT1 cadherin is the orthologue of Drosophila fat which encodes a tumour suppressor gene. However, human FAT1 has been identified as both a putative oncogene or a tumour suppressor gene in different cancer contexts. The FAT1 protein is a large 550 kDa transmembrane protein and very high expression occurs pre B- acute lymphoblastic leukaemia (ALL) patients harbouring the recurrent t(1:19) translocation. However, the regulation and oncogenic function FAT1 in t(1:19) positive and other forms of ALL remains unknown.
The specific aims of this project are to:
- determine whether expression of FAT1 provides a survival advantage in vivo using isogenic FAT1 CRISPR/Cas9 knockout vs wild-type 697 cell lines
- use an inducible lentiviral knockdown shRNAmir vector to specifically downregulate FAT1 in patient derived xenograft cell lines and determine whether this can decrease leukaemia engraftment and increase sensitivity to standard of care chemotherapeutic agents
- use novel anti-FAT1 antibody loaded nanoparticles to deliver chemotherapeutic agents to FAT1 positive acute lymphoblastic leukaemia cells.
Team
Team Leader
Research Officer
Dr Sofia Omari
Postdoctoral Scientist
Dr Jackie Huang
Students
Tommy Seo
News & blogs
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Cancer Council NSW funds exciting new research at Children's...
‘Moving the dial’ on treatment for childhood cancer
Get in touch
Do you have a question about our work? For any enquiries please don’t hesitate to contact us.
