Speaker
Description
Acute myeloid leukemia (AML) is an aggressive blood cancer driven by genetic and epigenetic alterations that disrupt normal hematopoiesis. Among these, the H3K27M mutation, originally identified in pediatric high-grade gliomas, reshapes gene repression programs by reducing global H3K27 trimethylation. Although rare, H3K27M mutations have been detected in preleukemic hematopoietic stem cells (HSCs) of AML patients, suggesting its role in early leukemogenesis and identifying it as a promising therapeutic target. Here, we investigated how H3K27M alters hematopoiesis using a longitudinal xenotransplantation model of human HSCs carrying either H3-K27M or wild-type H3. To quantify hematopoietic dynamics, we developed a collection of mathematical models representing alternative lineage hierarchies and fitted them to our longitudinal experimental data. Using information criteria and global sensitivity analysis, we identified the model that best capture blood dynamics in each condition. Our results show that H3K27M promotes the expansion of HSCs, common myeloid progenitors, and megakaryocyte-erythroid progenitors while inducing a delayed block in erythroid differentiation. By stimulating HSC proliferation, H3-K27M dynamics allowed us to distinctly characterize mouse HSC subpopulations (HSC1 and HSC2). Together, our results provide the first quantitative framework to reveal how H3K27M influences hematopoietic hierarchy roadmap and alters blood cell dynamics in preleukemia.
