Sometimes the whole is greater than the sum of its parts. Researchers at Cold Spring Harbor Laboratory have discovered that two harmful cell mutations enhance each other’s effects, contributing to the development of the deadly blood cancer acute myeloid leukemia (AML). The findings were published today in Nature.
Specifically, the presence of a mutation in IDH2 enhances the errors caused by a mutation in SRSF2, preventing cells in the bone marrow from maturing into the red and white blood cells an AML patient needs to overcome the disease. The team is now exploring ways to quickly shut this cooperation down, creating a powerful means to treat blood cancer.
“This all started when we were looking at patient data in The Cancer Genome Atlas and saw that again and again deadly cases of AML had both these mutations,” says senior author Omar Abdel-Wahab.
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Prior to this research, the only known similarity between the two mutations was that they are involved in pre-cancerous symptoms. But in many cases, the cause of the symptoms is not the cause of cancer itself. “Just because you see a mutation [in a sick patient’s cells] doesn’t really show that it’s directly contributing to the disease,” says Adrian Krainer.
The researchers knew that one of the two mutations in question, the SRSF2 gene, causes errors in a crucial process called RNA splicing, which can result in serious cell malfunction. Originally, they did not think splicing defects driven by SRSF2 were tied to AML because DNA tests show that the mutations are present in only 1% of AML patients. However, the Krainer lab, which specializes in RNA splicing, found that this problem is actually much more common, appearing in about 11% of AML patients.
Further experiments from Abdel-Wahab’s lab revealed that the severity of the identified SRSF2 splicing errors can be enhanced by the presence of a second mutation, IDH2, resulting in even more defective blood cells.
“So in some ways, these two genes, when defective, are cooperating,” Krainer says. “Now that we do know about this interdependence, we may find points where we can intervene.”
Image: In AML, defective blood cells (stained purple) are present. When the cells have a double mutation of both the IDH2 and SRSF2 genes (bottom right), the number of defective cells rises considerably, indicating a more lethal disease. Image courtesy of Krainer lab/CSHL, 2019.