Researchers Discover Timing of Genetic Mutation Affects Leukemia Severity

A recent study from the Icahn School of Medicine at Mount Sinai has revealed that the timing of a genetic mutation can significantly influence the aggressiveness of childhood leukemia. Led by Elvin Wagenblast, PhD, the research was published in the journal Cancer Discovery on March 15, 2025. The findings indicate that mutations occurring before birth result in more aggressive forms of leukemia, which grow faster and are more difficult to treat.

Dr. Wagenblast and his team employed advanced CRISPR/Cas9 genome-editing techniques to analyze how a specific mutation, the NUP98::NSD1 fusion oncoprotein, affects blood stem cells at various developmental stages. By examining cells from prenatal to postnatal and adolescent phases, the researchers created a unique experimental model that tracks the mutation’s behavior based on its timing.

The results were compelling. Stem cells generated during prenatal development demonstrated a propensity to transform into leukemia, leading to a more aggressive and primitive form of the disease. In contrast, stem cells produced after birth exhibited increased resistance to transformation and required additional mutations to become cancerous.

According to Dr. Wagenblast, “This work tells us that age matters at the cellular level. The same mutation behaves very differently depending on when it happens.”

Researchers observed that prenatal leukemia stem cells tend to be more dormant and rely on specific energy sources associated with cancer. This dormancy complicates treatment efforts, explaining the increased aggressiveness of leukemias that originate before birth, even when the genetic factors are identical.

The study also identified a distinct prenatal gene signature that correlates with adverse clinical outcomes in children diagnosed with leukemia. This discovery highlights the potential for improved diagnostic tools capable of identifying high-risk patients earlier in their treatment journey.

The team tested various therapies against the most aggressive leukemia stem cells and found that these cells were particularly vulnerable to venetoclax, a drug already approved by the Food and Drug Administration. Combinations of venetoclax with standard chemotherapy were shown to significantly reduce the aggressiveness of leukemia in experimental models.

Dr. Wagenblast noted, “These findings give clinicians mechanistic support to use venetoclax combinations in NUP98-rearranged acute myeloid leukemia, particularly in younger patients whose disease likely started before birth.”

The implications of this research extend beyond immediate treatment options. By understanding the developmental timing of mutations, healthcare professionals can potentially select therapies that are more effective and minimize the trial-and-error approach that often characterizes leukemia treatment. This study represents a shift in how scientists view childhood cancer, emphasizing that the timing of the first mutation can fundamentally influence disease biology, treatment resistance, and relapse risk.

Future research will focus on developing therapies that directly target the metabolic processes unique to prenatal-origin leukemias. The goal is to eliminate leukemia stem cells while preserving healthy blood stem cells, thus improving treatment outcomes for affected children.

This study involved collaboration with institutions such as the Fred Hutchinson Cancer Center, Children’s Hospital of Philadelphia, and Cincinnati Children’s Hospital, and was supported by funding from the National Institutes of Health and various private foundations.