By analyzing single-cell gene expression data from their models, the investigators identified a prenatal gene signature that predicts whether a child’s leukemia likely began before birth. In patients, this signature correlated with significantly worse clinical outcomes. 

“This work tells us that age matters at the cellular level,” said Dr. Wagenblast. “The same mutation behaves very differently depending on when it happens. Understanding this gives us a new way to identify the highest-risk patients and to tailor therapies that go beyond standard genetic classifications.” 

The team tested therapies against the most aggressive leukemia stem cells and discovered that these cells were especially vulnerable to venetoclax, a Food and Drug Administration-approved drug already used in the clinic. Venetoclax-based combinations, including with standard chemotherapy, significantly reduced leukemia aggressiveness in the experimental models.

“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,” said Dr. Wagenblast. 

Conceptually, the study shifts how scientists understand childhood cancer. The developmental timing of the first mutation is not a minor detail. It fundamentally shapes disease biology, treatment resistance, and relapse risk. The research opens the door to new diagnostic tools that can identify prenatal-origin leukemias, venetoclax-based combination therapies that more precisely target vulnerable leukemia stem cells, and clinical trials that incorporate developmental timing into risk assessment.

The study was conducted in collaboration with the Fred Hutchinson Cancer Center, Children's Hospital of Philadelphia, and Cincinnati Children’s Hospital Medical Center, with funding from the National Institutes of Health, and private foundations. 

The team now plans to develop therapies that more directly target the metabolic program unique to prenatal-origin leukemias, with the goal of selectively eliminating leukemia stem cells while sparing healthy blood stem cells.