Most blood cancers arise when uncontrolled growth of abnormal blood cells overtakes healthy blood cell development. Understanding this process is critical to developing new treatments for these cancer patients, who have difficulty fighting off infections or forming blood clots. Omar Abdel-Wahab, MD (Damon Runyon Clinical Investigator ‘13-‘16), from Memorial Sloan Kettering Cancer Center, and Adrian R. Krainer, PhD, from Cold Spring Harbor, collaborated to uncover how a genetic mutation can cause RNA messages to be blocked, triggering biological steps that lead to most leukemias.
The deadly chain of events begins with RNA splicing, a process that converts messages from DNA into instructions for making proteins in a cell. Errors in RNA splicing can result in poorly formed proteins that are unable to do their job. Dr. Abdel-Wahab, a hematological oncologist, has shown in previous research that when splicing isn’t done properly, it can lead to cancer. “RNA splicing factor mutations are seen in virtually all forms of leukemia, both chronic as well as acute myeloid leukemias and also even chronic lymphocytic leukemia,” he said.
The latest findings show that in blood cancers a process associated with splicing, called Nonsense-Mediated mRNA Decay (NMD), is overly active. After splicing converts DNA messages, the NMD process normally serves as “quality control,” destroying messages that contain mistakes before broken proteins are made.
The researchers discovered that when a gene called SRSF2 is mutated, NMD destroys many RNA messages that are important for healthy blood cell production. The overly active NMD results in more sickly or immature cells—a hallmark of blood cancers. Scientists have seen other cancers manipulate NMD into protecting solid tumors, but this is the first evidence of NMD contributing to blood cancers. This research suggests that drugs targeting the defective splicing factors may provide a novel treatment approach.
Read More: Mutation Disrupts DNA Messages in Blood Cancers
Published in Genes and Development
