Seminal Study Reveals a Hidden Culprit in the Development of Adult Blood Cancers

Published November 2021 | Cell Stem Cell

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 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 poor outcomes.

“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 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 says.

By generating mice with both the inherited and acquired DDX41 mutations, the researchers found that the combination disrupts 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.

“We are in the early stages of understanding this complex disease,” Chlon says. “If we can determine why these patients’ cells are defective, that would go a long way towards developing treatment or prevention strategies.”