A study from the Icahn School of Medicine at Mount Sinai has found that the timing of a genetic mutation plays a key role in determining how aggressive childhood leukemia becomes. The research, led by Dr. Elvin Wagenblast and published in Cancer Discovery, examined why children with the same leukemia-causing gene mutation can have very different outcomes.
The team used CRISPR/Cas9 genome-editing technology to introduce the NUP98::NSD1 fusion oncoprotein into human blood stem cells at various developmental stages. This approach allowed them to create a model tracking how the same mutation behaves depending on when it occurs in life.
Their findings showed that when the mutation happens before birth, it leads to a more aggressive and harder-to-treat form of leukemia. Prenatal-origin leukemia stem cells were found to be more dormant and dependent on specific energy sources unique to cancer, making them less responsive to standard treatments. In contrast, mutations occurring after birth required additional changes for leukemia to develop and resulted in less aggressive disease.
By analyzing single-cell gene expression data, researchers identified a prenatal gene signature that predicts whether a child's leukemia likely began before birth. This signature was linked to worse clinical outcomes among patients.
Testing therapies against these aggressive stem cells revealed that they are particularly sensitive to venetoclax, an FDA-approved drug already used in some cancer treatments. Combinations of venetoclax with standard chemotherapy significantly reduced disease aggressiveness in 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.
The study suggests that knowing when leukemia begins could help doctors select more effective treatments earlier and potentially reduce relapse rates. It also opens possibilities for new diagnostic tools and therapies targeting prenatal-origin leukemias.
The research involved collaborations with Fred Hutchinson Cancer Center, Children's Hospital of Philadelphia, and Cincinnati Children's Hospital and received funding from the National Institutes of Health and private foundations.
