Overall research focus: Investigating the role of the bone marrow microenvironment in the development, progression and relapse of haematological malignancies

Project 1: Investigating mechanisms of relapse in childhood B-cell Acute Lymphoblastic Leukaemina (B-ALL)

B-cell acute lymphoblastic leukaemia (B-ALL) is the most common form of childhood cancer in Australia, accounting for approximately 27% of all cancers in children. Disease relapse, which occurs in 10-15% of paediatric patients, is the greatest cause of treatment failure, and is associated with a high mortality rate. Despite significant international efforts to identify children at high risk of relapse, many children still relapse and die from this disease.

It is widely understood that B-ALL cells “hijack” normal cellular processes within the bone marrow, where they reside to create an environment that supports ALL cells growth and protects tumour cells from chemotherapy. These chemotherapy-resistant ALL cells are the likely source of relapse.

Our group has recently identified a diagnostic gene signature in patient samples that can predict relapse. Within this gene signature, CKLF1, is highly expressed. To date, little is known about the function of CKLF1. My work is centred on uncovering the role CKLF1 plays in promoting B-ALL relapse and determining if specific targeting of CKLF1 may represent a viable therapeutic strategy to limit relapse.

Project 2: Identification of microenvironmental factors that drive multiple myeloma (MM) disease progression

Multiple Myeloma (MM) is a haematological malignancy, characterised by the uncontrolled proliferation of antibody producing plasma cells within the bone marrow (BM). MM is the second most common blood cancer, accounting for approximately 15% of all blood cancers in Australia. In recent years, significant advances have been made in the treatment of MM, however almost all patients will eventually relapse and succumb to their disease. Therefore, new ways of treating myeloma patients that improve their disease free survival and improve their quality of life are urgently needed.

Like ALL, MM develops almost exclusively within the BM wherein tumour cells interact with a wide range of accessory cells, including inflammatory and immune cells. Accessory cells within the BM have been well-documented to support the development and progression of MM, however the identity of the specific secreted factors present within the bone marrow microenvironment that are essential for the development of MM are currently unknown.

My research focusses on:

1. Identifying and characterising a role for BM macrophages in MM disease development. My studies have already demonstrated a requirement for these innate immune cells in MM development in mouse models. Studies are continuing to define mechanisms of macrophage-mediated support of tumour growth and to identify key secreted factors that might be targeted to alter macrophage function.
2. Identifying the role of the inflammatory enzyme, myeloperoxidase (MPO) in MM development. Our recent studies using animal models of MM suggest that inhibition of MPO can limit the progression of MM. Further studies will investigate the efficacy of a novel MPO inhibitor (which has already passed Phase I clinical studies) in treating MM while simultaneously teasing out the mechanisms employed by MPO to support MM tumour growth.