Team IDs mechanism underlying rare children’s blood cancer

Jan. 25, 2022

Researchers have identified a mechanism through which two antiviral genes, when mutated, promote a childhood cancer called pediatric myelodysplastic syndrome (MDS), according to a news release from the University of Texas Health Science Center at San Antonio (UT Health San Antonio).

Researchers from UT Health San Antonia, Oklahoma State University, and Cornell University collaborated on the study, which was published in Proceedings of the National Academy of Sciences.

When normal, the genes, called SAMD9 and SAMD9L, suppress tumor formation and help protect against virus infection. They are effective and selective sentinels.

“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 at UT Health San Antonio. “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.”

Since 2017, studies have found that about 8% of pediatric MDS patients have mutations in the two genes. That makes SAMD9/SAMD9L errors the most common currently known cause of MDS in children. These children have fewer immune cells than normal and a high tendency to develop acute myeloid leukemia.

The new study contributes two key findings:

  • Patient-derived SAMD9/SAMD9L mutations cause a stall in protein synthesis in cells and prompt a stress response to abnormal protein synthesis. This could largely explain why children with the mutations have the underdeveloped immune system. Other studies in the last few months have hinted at protein synthesis as the problem.
  • SAMD9 and SAMD9L proteins have a specific region that is very critical for their function. When the researchers deactivated this region, they stopped the toxic effects of the mutated proteins.

The team also found that this protein region performs the toxic function through binding to nucleic acids, which are molecules that store and express genetic information.

MDS is characterized by abnormal stem cell function in the bone marrow, resulting in lower numbers of blood cells than normal. The blood cells are poorly formed and don’t work well. Although rare, MDS risk increases with age.

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