A team of researchers from Memorial Sloan Kettering Cancer Center (MSK) and Weill-Cornell Medical College have identified, for the first time, a new molecular pathway that is required for acute myeloid leukemia (AML) development. This work could provide a rationale for targeting the RNA methylation program in myeloid leukemia.
This study demonstrates, for the first time, that enzymes that control RNA methylation (N6-methyladenosine or m6A) are highly upregulated in AML cells, identifying them as a molecular pathway that is required for AML development. Based on an analysis of the Cancer Genome Atlas Research Network data sets, genes encoding m6A writer complex proteins were expressed higher in AML compared with all other cancers, suggesting that these enzymes may play a significant role in leukemia.
Through genetic approaches, Michael Kharas, PhD, co-corresponding author and a cancer biologist at MSK, and colleagues showed that when these enzymes were depleted, the leukemia cells stopped growing, lost their leukemia phenotype, and underwent cell death. In addition, the scientists found that a key enzyme that writes these marks on RNA was essential for the development of leukemia in animal models. Together, these data point to a new concept for chemotherapy: blocking RNA methylation codes to target leukemia.
In this paper, the team also provides mechanistic insights into how modifications on mRNA can control RNA metabolism in the context of myeloid leukemia.
“We work every day in my lab at MSK studying RNA-binding proteins and how those pathways can be become altered in myeloid leukemia in the hopes of improving the understanding of cancer pathogenesis and treatment,” explained Dr. Kharas. “We were excited to discover that RNA modifications dictate leukemia survival, a finding that unveils the possibility to target this novel pathway in AML.”
AML, one of the most common leukemias in adults, is diagnosed in nearly 15,000 people in the United States each year. An aggressive blood cancer, AML has proved to be difficult for doctors to assess and treat, with the majority of patients relapsing from their disease. Scientists and clinicians are eager to find new ways to stop the growth of this cancer, but until now, molecular pathways have been elusive.
The world of RNA regulators in stem cell biology and their potential as therapeutic targets in cancer and regenerative medicine are virtually unexplored. While m6A has been recently identified as a regulator of cell fate and differentiation, the role for m6A in normal blood development and in AML has not been known. In his lab at MSK, Dr. Kharas studies RNA regulators of self-renewal in both normal and leukemic hematopoiesis, with a specific interest in identifying novel RNA-binding proteins and regulators in myeloid leukemia. Most recently, Dr. Kharas teamed up with Samie Jaffrey, MD, PhD, of Weill-Cornell Medical College, to explore the emerging links between m6A and misregulated mRNA methylation in cancer.
This preclinical work was conducted in the lab using genetic approaches and confirmed in animal models using human AML cell lines and primary patient samples. Further studies are warranted to confirm the mice findings in humans and the therapeutic potential of targeting this pathway.
“m6A Regulates Differentiation State and mRNA Translation in Myeloid Leukemia” appears in Nature Medicine on September 18, 2017.
Michael Kharas, PhD, cancer biologist at Memorial Sloan Kettering Cancer Center, served as co-corresponding author on this paper, along with Samie Jaffrey, MD, PhD, of Weill-Cornell Medical College.