Acute myeloid leukemia (AML) is a heterogeneous disease with considerable diversity in terms of genetic abnormalities. Mutations of CCAAT enhancer binding protein alpha (CEBPA), a tumor suppressor, are found in about 10% of human AML patients. In two separate studies on CEBPA mutations in AML subtypes, researchers successfully identified and validated a gene known as Sox4 as a potential therapeutic target along with a class of anticancer drugs—histone deacetylase (HDAC) inhibitors—as potential candidates in the treatment of AML subtypes.

Both research teams, comprising international scientists, were led by Professor Daniel Tenen, MD, who is director, Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore and also affiliated with Harvard Medical School in Boston, Massachusetts.

In the first study, published in Cancer Cell (2013;24[5]:575-588), researchers discovered a molecular target for CEBPA mutations. When they targeted Sox4, it effectively perturbed the major leukemogenic phenotypes in human patient samples of mutated CEBPA AML.

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Although CEBPA mutations have been studied for decades, the precise oncogenic pathway and the role of their downstream targets are still poorly understood. This is the first study that identified a molecular target downstream of CEBPA mutations.

By identifying the failure to suppress oncogene Sox4 expression as the underlying mechanism of CEBPA mutant-transformed leukemia stem cells (LSCs), Sox4 was highlighted as a potential therapeutic target for a subtype of AML. The discovery provides a direct route for the treatment of such leukemias and is a big step forward. Currently, therapeutic options are limited for this subtype of AML.

In the second study, published in Haematologica (2013; doi:10.3324/haematol.2013.093278), the scientists identified a group of genes that were not properly expressed in a subgroup of AML patient samples. They demonstrated that HDAC inhibitors were able to reactivate expression of these genes and, as such, could potentially be used to treat certain types of AML.

The research team examined the blood samples of more than 500 patients with newly diagnosed AML. They found that a group of genes, known as the CEBPA signature, was not properly expressed in 20% of the blood samples. The CEBPA signature was found to be responsible for blocking the growth of granulocytes and impeding their ability to mature into healthy blood cells.

The scientists further tested the effects of HDAC inhibitors, which are a class of anticancer drugs that trigger the production of proteins. Using laboratory models and blood samples from the patients, these inhibitors were tested on the subtype of AML that lacked the CEBPA signature. The researchers found that the HDAC inhibitors were able to reactivate the expression of the CEBPA signature and promote the growth of healthy blood cells. This demonstrated that the HDAC inhibitors are potential drugs for the treatment of this AML subtype.