Research into the aggressive behavior of certain adult B-acute lymphoblastic leukemias has yielded a potential new prognostic biomarker and a promising new therapeutic target.
Although B-acute lymphoblastic leukemia is highly curable in children, the disease is usually fatal in adults. Researchers have yet to identify why this is so. Part of the explanation for the worse outcomes in adults is the higher frequency of genetic alterations associated with unfavorable prognosis.
To improve understanding of why these genetic alterations are associated with poor outcomes, the research team studied 215 diagnostic specimens obtained from adults with B-acute lymphoblastic leukemia who were participating in a large Eastern Cooperative Oncology Group phase III clinical trial. The researchers used an integrative epigenomics study to decode the instructions that determine how the cells behave.
Many cancers have genetic alterations that work in conjunction with epigenetic changes to promote cancerous behaviors. Among the specimens of B-acute lymphoblastic leukemia, many of the leukemia’s negative traits were a result of changes in the epigenetic code. Many cases involved epigenetic changes that were directly linked to the proteins generated from the genetic alterations. These changes could be used to identify key master regulations required for the leukemic cells to live.
“For example, we found that a cell surface molecule called CD25 was an extremely powerful indicator of the presence of the most aggressive and fatal cases,” said Ari Melnick, MD, of Weill Cornell Medical Center.
The researchers also discovered that abnormal forms of E2A and MLL proteins occurring in B-acute lymphoblastic leukemias directly reprogram epigenetic settings at their binding sites throughout the genome. Most notably, mutant forms of MLL epigenetically reprogrammed leukemia cells to express BCL6, a powerful oncoprotein. BCL6 was required to maintain the proliferation and survival of leukemia cells.
“We then designed inhibitors of BCL6 and showed that we could kill leukemia cells from patients enrolled in the clinical trial by blocking its function,” Melnick said.
These results have led the researchers to plan to use CD25 as a biomarker to identify those patients who have the worst disease in the next set of clinical trials, and to tailor treatment appropriately. Further, BCL6 inhibitors are currently being translated for use in humans, and the research team hopes to develop clinical trials that target BCL6 in leukemias with rearranged MLL.
Melnick explained, “These results will ultimately lead to biomarkers that help guide treatment and to the development of therapies that will be more effective for patients with this aggressive form of leukemia.”
This research was published in Cancer Discovery (2012; doi:10.1158/2159-8290.CD-12-0208).