Pediatric myelodysplastic syndrome (MDS) is a rare disease of the blood, only occurring in four out of every one million children. MDS develops in the bone marrow and occurs when the bone marrow does not properly produce sufficient numbers of healthy red blood cells, white blood cells, and platelets. With this disease, the blood cells lose their ability to mature and function properly. Researchers at the University of Texas Health Science Center at San Antonio (UT Health San Antonio), Oklahoma State University, and Cornell University report they have identified a mechanism through which two antiviral genes, when mutated, promote MDS. When normal, the genes, called SAMD9 and SAMD9L, suppress tumor formation and help protect against virus infection. They are also effective and selective sentinels.

The findings are published in the journal Proceedings of the National Academy of Sciences in a paper titled, “Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L.”

“SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors,” the researchers wrote. “SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes.”

“Normally those two genes are silent in the cells, only becoming activated when they encounter infection,” said senior author Yan Xiang, PhD, professor of microbiology, immunology, and molecular genetics in the Joe R. and Teresa Lozano Long School of Medicine. “However, if an individual has a mutation in these two genes, they are turned on, even without infection. And that can create a lot of diseases.”

“We obtained a crystal structure of the region to know what it looks like,” Xiang said, referring to X-ray crystallography studies showing the 3D architecture of the region.

“Since we have the structure of that region, and we know its function, we fully believe we have identified a key therapeutic target for pediatric myelodysplastic syndromes derived from SAMD9 and SAMD9L mutations,” Xiang said. “We hope to eventually develop a molecule to target that region.”

Their identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases.