Acute myeloid leukaemia (AML), a cancer arising from the abnormal growth in the blood-forming tissue of the bone marrow, is the most common type of acute leukaemia affecting adults. It can lead to death within months, or even weeks if left untreated. The identification of a therapeutic target and anti-cancer drugs by a group of international scientists led by the Cancer Science Institute (CSI) Singapore at NUS may bring reprieve for such patients.
Research has shown genetic abnormalities in AML, with mutations of CEBPA, a tumour suppressor, found in about 10 per cent of patients. Two separate studies by the team on CEBPA mutations in AML subtypes successfully determined an oncogene known as Sox4 as a potential therapeutic target, and a class of anti-cancer drugs, histone deacetylase (HDAC) inhibitors, as potential candidates in the treatment of certain AML.
Both work conducted by investigators from Singapore, Austria, Czech Republic, Italy, the Netherlands, Sweden, the UK and US, was headed by Professor Daniel Tenen, Director of CSI Singapore.
The team discovered a molecular target for CEBPA mutations by showing that targeting Sox4 significantly affects the major types of leukaemia in mutated human CEBPA AML samples. This is the first study identifying a molecular target downstream of CEBPA mutations, where the failure to suppress Sox4 expression leads to the progression of leukaemia. The information, published in leading journal Cancer Cell, provides knowledge that can be tapped for approaches to address this subtype of AML.
The researchers will continue to look into the downstream signalling components of Sox4 and examine the effect of pharmaceutical drugs on these pathways, with a view to developing novel therapeutic drugs for cancer.
The second breakthrough came when the scientists pinpointed a group of genes not properly expressed in a subgroup of AML patient samples. Tests of HDAC inhibitors – a class of anti-cancer drugs – on the subtype of AML using laboratory models and patient blood samples found that the inhibitors were able to reactivate the expression of the CEBPA genes. This spells exciting possibilities that the inhibitors could potentially be used as drugs in the treatment of certain AML. The work was first published online in Haematologica.
As HDAC inhibitors have complex mechanisms of action, the researchers plan to further delve into the behaviour of these drugs at the molecular level so as to establish ways to promote the growth of healthy blood cells.
Prof Tenen noted: “Up to now, therapeutic options for AML are very limited. By understanding oncogenic pathways and the signatures which respond to specific enzyme inhibitors, we can build up our knowledge and understanding towards the development of more efficient drugs. We hope to apply similar approaches to identify new therapeutic avenues for other types of AML.”
National University of Singapore.