Fetal Hematopoietic Stem Cell Development And Childhood Leukemia Initiation

Most pediatric leukemias are considered to originate pre-natally.However,the exact place and time and mechanism in which the initiating leukemic mutations occur remain much unknown.Here,we addressed these issues by investigating the characteristics and genome stability of fetal hematopoietic stem and progenitor cells(HSPCs).We first analyzed the lineage components of FL from 12.5 days post-fertilization(dpf)to 18.5 dpf.The myeloid and lymphoid cells were dynamic in absolute number and ratio.The largest difference was between 12.5 and 16.5 dpf.The FL-HSPCs at these two time points were then respectively transplanted into the recipients.The difference in lineage reconstitution was undetectable at week 4 post-transplantation and afterward,indicating that the BM environment assimilated the transplanted cells.Profiling lineage-specific genes of input and output HSPCs showed that the expression levels were much different in the former and almost the same in the engrafted HSPCs.Therefore,the recipient BM microenvironment could determine the developmental lineage-trends of FL-HSPCs.Next,we determined that the chromatin in the HSPCs that initially migrate from placenta to fetal liver(12.5dpf)is most fragile and that the induced alterations at the period could be retained to the postnatal bone marrow.Consistently,compared the transcriptome by using NGS between HSPCs in different developmental microenvironment,we identified that chromatin-stabilized factors are insufficiently expressed in the HSPCs of 12.5 dpf FL,and the Tlr4 signal pathway inactivated in HSPCs of 12.5dpf FL regulated the genome stability.These findings are important in studies of etiology and prevention of childhood leukemia.