PNAS discovers pathogenesis of rare childhood blood cancer

UT Health San Antonio researchers report this week in the Proceedings of the National Academy of Sciences that they have discovered a mechanism by which This mechanism, when two antiviral genes are mutated, promotes a childhood cancer called pediatric myelodysplastic syndrome (MDS)

Normally, genes called SAMD9 and SAMD9L suppress tumor formation and help prevent viral infection

"Normally, these two genes are silent in the cell and are only activated when they encounter an infection," said senior author Xiang Yan, Ph.

Since 2017, studies have found that about 8 percent of children with MDS have mutations in these two genes

The new study contributed two key findings:

• Patient-derived SAMD9/SAMD9L mutations result in arrest of protein synthesis in cells and a stress response to abnormal protein synthesis

  
  

• The SAMD9 and SAMD9L proteins have a specific region that is critical to their function

  
  

The team also found that this region of the protein exerts its toxic function by binding to nucleic acids, the molecules that store and express genetic information

"We obtained the crystal structure of the region to see what it looked like," Dr.

Dr Xiang said: "Because we have the structure of this region and we know its function, we are fully confident that we have identified a key therapeutic target for the treatment of myelodysplastic syndromes in children derived from SAMD9 and SAMD9L mutations

To date, bone marrow transplantation has been the only treatment option for children with SAMD9 and SAMD9L mutations

MDS is characterized by abnormal function of bone marrow stem cells, resulting in lower-than-normal numbers of blood cells

Pediatric MDS is rare in children

article title

Structure and Function of an Effector Domain in Antiviral Factors and Tumor Suppressors SAMD9 and SAMD9L