An international team of researchers working in the Boston and Singapore labs of Harvard Stem Cell Institute (HSCI) Blood Program leader Daniel Tenen, MD, recently identified new candidates for the treatment of an acute myeloid leukemia (AML) subtype caused by mutations of CEBPA, a tumor suppressor. The findings were published in two separate studies:

• On November 11, 2013, in Cancer Cell, a publication of Cell Press, the researchers demonstrated how they found and validated the first molecular target for CEBPA mutations, a gene known as Sox4.
• On October 31, 2013, in Haematologica, the journal of the European Hematology Association and the Ferrata-Storti Foundation, the investigators showed how a class of anti-cancer drugs, called histone deacetylase inhibitors, could be potential candidates for AML treatment.

Breakthrough study validates Sox4 as potential therapeutic target

In the Sox4 study, the researchers found that silencing the gene in mice with the CEBPA-mutation subtype of AML reduces leukemia symptoms The CEBPA mutation, found in ~10 percent of AML patients, causes normal blood-forming stem cells to stop differentiating and endlessly divide.

The research team also showed how certain AML symptoms of human patient cells can be reversed upon the removal of Sox4 using a transplant setting, a very difficult and rare piece of scientific data that demonstrates the therapeutic potential of Sox4. The positive results make the investigators believe that future study of the Sox4 and its related signaling pathways could lead to the development of new cancer drugs.

“We are interested in molecular targets that function at the stem cell level,” said Hong Zhang, PhD, a research fellow at Beth Israel Deaconess Medical Center (BIDMC) and first author of the Cancer Cell study. “As far as we know, for this subtype of leukemia, SOX4 is the first target identified that’s been proven to work in both mouse model and human patient samples.”

Zhang worked under the guidance of senior author Daniel Tenen, MD, who heads laboratories at BIDMC and the Cancer Science Institute of Singapore, where he is director, at the National University of Singapore. David Scadden, MD, HSCI co-director and Harvard Medical School Gerald and Darlene Jordan Professor of Medicine at Massachusetts General Hospital was also involved in the research.

The research was primarily supported by the HSCI and the National Institutes of Health. Additional support was received from the Czech Ministry of Youth, Health and Sports, a Collegio Ghislieri fellowship, the Austrian Research Foundation, the European Union, a Societa’ Italiana di Ematologia Sperimentale, the Jose Careras Leukemia Foundation, FAMRI CIA, and Leukemia Lymphoma Research.

Citation: Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia. Cancer Cell. November 11, 2013

New research identifies histone deacetylase inhibitors as potential candidates in treatment of AML

In the Haematologica study, the scientists identified a group of genes related to CEBPA that were not properly expressed in a subgroup of AML patient samples. They demonstrated that histone deacetylase (HDAC) inhibitors were able to reactivate expression of these genes and as such, could potentially be used as drugs in the treatment of certain AML.

The research team found that the CEBPA-related genes were not properly express in 20 percent of the blood samples of more than 500 patients who were newly diagnosed with AML Using patient blood samples, the investigators found that HDAC inhibitors were able to reactivate the expression of the CEBPA–related genes and promote the growth of healthy blood cells, demonstrating the HDAC inhibitors as potential drug targets for the treatment of the AML subtype.

 “Up to now, therapeutic options for AML are very limited, “Tenen said. “By understanding oncogenic pathways and the signatures that 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.”

The research was supported by the MSMT Navrat, the National Institutes of Health, and a Singapore Translational Research (STaR) Investigator Award.

Citation: The gene signature in CCAAT enhancer binding protein α dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors. Haematologica. October 31, 2013