Mount Sinai researchers uncover why the same leukemia-causing mutation can lead to dramatically different outcomes in children: the timing of when the mutation first appears during development matters. The team from Icahn School of Medicine at Mount Sinai reports in Cancer Discovery that leukemias driven by the NUP98::NSD1 fusion arise before birth tend to be more aggressive, grow faster, and resist treatment compared with those that originate after birth. This adds a crucial dimension to precision medicine for childhood leukemia.
Led by Elvin Wagenblast, PhD, Assistant Professor of Oncological Sciences and Pediatrics, the study used advanced CRISPR/Cas9 genome-editing to model acute myeloid leukemia (AML) at multiple developmental stages in human blood stem cells. By introducing the NUP98::NSD1 fusion into cells derived from prenatal through adult development, the researchers created a first-of-its-kind humanized model that demonstrates how the same genetic mutation can behave very differently depending on when it occurs in life.
Key findings show that prenatal-emerging leukemia stem cells readily transform into leukemia and exhibit a highly aggressive, primitive profile. In contrast, postnatal cells require additional mutations to become cancerous and are more resistant to transformation. Prenatal-origin leukemia stem cells were found to linger in a quiescent state and depend on metabolic pathways that are distinct from later-onset leukemias, helping explain why prenatal cases can be tougher to treat despite sharing the same genetic change. The prenatal signature also predicts worse clinical outcomes in patients, linking developmental timing to prognosis.
According to Wagenblast, “age matters at the cellular level. The same mutation behaves very differently depending on when it happens, which opens new avenues to identify high-risk patients and tailor therapies beyond standard genetic classifications.”
Therapies tested against the most aggressive leukemia stem cells revealed a particular vulnerability to venetoclax, an FDA-approved drug already used clinically. Venetoclax-based combinations, especially when paired with standard chemotherapy, significantly reduced the disease’s aggressiveness in the models.
Wagenblast notes, “These results provide mechanistic support for using venetoclax combinations in NUP98-rearranged AML, particularly in younger patients whose disease likely began before birth.” More broadly, understanding when leukemia begins could help clinicians choose more effective therapies earlier, reducing trial-and-error approaches and lowering relapse risk.
The study reframes childhood cancer biology by showing that the developmental timing of the first mutation is a fundamental driver of disease behavior, treatment response, and relapse risk. It also paves the way for new diagnostic tools to identify prenatal-origin leukemias, venetoclax-based regimens to target vulnerable leukemia stem cells, and clinical trials that incorporate developmental timing into risk stratification.
Looking ahead, the team plans to develop therapies that specifically disrupt the metabolic program characteristic of prenatal-origin leukemias, with the goal of eradicating leukemia stem cells while sparing healthy ones.
Collaborators include Fred Hutchinson Cancer Center, Children’s Hospital of Philadelphia, and Cincinnati Children’s Hospital, with support from the National Institutes of Health and private foundations.
About Mount Sinai
The Icahn School of Medicine at Mount Sinai is a leading center for research, education, and clinical care in New York City, collaborating with Mount Sinai Health System’s seven hospitals. It conducts extensive translational research and trains thousands of students, residents, and fellows across multiple degree programs, with substantial NIH funding and a broad commitment to bringing scientific discoveries to patient care.
