Cancer researchers discovered in 2015 that inherited mutations in the DDX41 gene cause predisposition to the development of adult blood cancers. A seminal study led by Timothy Chlon, PhD, goes a long way toward answering the question, “why?” The study was published in Cell Stem Cell (Nov. 4, 2021).  The DDX41 mutation is present in a cohort of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Despite possessing the mutated gene in all of their cells from birth, these individuals do not develop the disease until their 60s and 70s. Five-year survival rates of patients with these diseases are poor—about 30% overall. Chlon wanted to understand how the DDX41 mutations contribute to the pathogenesis that causes bone marrow failure and preleukemia syndromes. He began the study as part of his post-doctoral fellowship at Cincinnati Children’s while working under Daniel Starczynowski, PhD. Starczynowski’s research lab focuses on inflammatory and innate immune signaling pathways that are hijacked in leukemia cells.  

“We hypothesized that the DDX41 defect drove the predisposition by dysregulating inflammatory and innate immune signaling pathways,” Chlon says. “But instead, we found that an obvious defect in ribosome biology was responsible for the pathogenesis.” 

Chlon’s team modeled the disease by generating a series of sophisticated mouse models with mutations in DDX41 similar to those seen in human patients. “One interesting aspect of these diseases is that in over 70% of MDS and AML patients with an inherited DDX41 mutation, a second DDX41 mutation is observed in a small proportion of their diseased bone marrow cells,” he explains.  

By generating mice with both the inherited and acquired DDX41 mutations, they found that the combination of these mutations causes a defect in the production of ribosomes, the cellular machines for making new proteins. The lack of ribosomes caused a defect in the production of new blood cells, creating an environment for leukemia to develop.  

“In the models we developed that included the second mutation, all of the dysfunction we observed in blood stem cells could be explained by the ribosome effect,” Chlon says. “We went on to show that these cells had defects in producing a type of RNA called small nucleolar RNA, which is essential for ribosome production.” 

Additionally, Chlon created complex mouse models that capture the heterogeneous nature of cells present in patient bone marrow. They observed that when cells bearing the two DDX41 mutations were mixed with cells possessing just one DDX41 mutation, as would occur in patients, facets of the disease were recapitulated in the mice. 

Chlon is emerging as a leading expert on the genomic predisposition to MDS. He has spoken on the topic at multiple conferences, including those sponsored by the American Society of Hematology and the Aplastic Anemia & MDS International Foundation.  

“We are in the early stages of understanding this complex disease, but I am excited about this research because it presents a challenging biological question that directly impacts patients’ lives,” Chlon says. “If we can determine why these patients’ cells are defective, that would go a long way towards developing treatment or prevention strategies for this disease.” 

The findings of the study are summarized in this schematic. Blood stem cells carrying two mutant copies of DDX41 contribute to disease by both failing to make new blood cells themselves and also affecting the efficiency of neighboring blood stem cells.

Learn more about the Chlon lab.