Fev Expression Is Functionally Required for Fetal HSCs and LSCs Indicating Prenatal Origin of Leukemia

Cancers, particularly in the childhood and adolescence, can originate prenatally or postnatally. How to distinguish however and what clinical implication of the distinct origin of cancers remains unknown. Here we have identified and characterized transcription factor fev an indicator of prenatal origin of leukemia in the human context of normal and leukemic hematopoiesis. Fev is expressed in fetal and neonatal and not in adult hematopoietic cells. Functional assays showed fev is essential for self-renewal in fetal HSCs. More interestingly, fev is expressed in leukemic cells of some cell lines and patients, which is associated with more frequent relapse. Fev-knockdown in leukemic cells markedly compromised their capacity of leukemic reconstitution in xenograft recipients. Leukemogenic targeting experiments by forced expression of MLL-AF9 or N-Myc showed fev-regulated self-renewal is retained from fetal HSCs rather than reactivated in adult HSCs. Therefore, fev-expression can distinguish LSCs from normal HSCs and indicate its prenatal origin.