Dr Pasquale Fedele
Researcher: Dr Pasquale Fedele
Institute: Walter and Eliza Hall Institute of Medical
Project title: Investigating the role of
and XBP1 as potential tumour suppressors
in multiple myeloma
Disease focus: Myeloma
Annual Funding: $60,000
Funding period: 2015-2017
To better understand how myeloma develops, Dr Pasquale Fedele is studying two genes – PRDM1 and X-box binding protein 1 (XBP1) – that are important for normal plasma cell development and function.
Plasma cells are highly specialised cells that produce antibodies, helping the body’s immune system to recognise and destroy germs when they invade the body. However, damage to the DNA of plasma cells can lead to myeloma.
“The aim of this project is to understand how PRDM1 and XBP1 control normal plasma cells as well as how mutations to these genes contribute to myeloma development,” said Dr Fedele.
“Critically, we suspect that the loss of either of these genes may play an important role in myeloma cells becoming resistant to treatment with an important class of medications called proteasome inhibitors, such as bortezomib (Velcade®).
“If we can understand the potential effects of these mutations, it will help us better treat myeloma with combination therapies.”
In 2011, a research team (Chapman et al.) used next-generation sequencing to compare the DNA from 38 myeloma tumours with the patients’ normal DNA. The team discovered 11 genes commonly mutated in myeloma. One of these genes was PRDM1.
The PRDM1 gene produces a protein known as BLIMP-1, which is a ‘master regulator’ of plasma cell development.
Dr Fedele is continuing the work of his supervisor, Walter and Eliza Hall Institute of Medical Research (WEHI) Molecular Immunology Division Head, Professor Stephen Nutt, in looking at the role of BLIMP-1 in myeloma.
Although not one of the 11 commonly mutated genes, the XBP1 gene was highlighted as a gene of interest by the research team. This gene produces the XBP1 protein, which is essential for normal antibody production in plasma cells.