Proposed leukemogenesis model of the aberrant fetal-to-adult hematopoiesis switch in JMML. Fetal and adult hematopoiesis are governed by a developmental/age-specific molecular driving force and executed by fetal-selective genes and adult-necessary genes in hematopoiesis (eg, SOX17, LIN28B, HMGA2, and EZH2 for fetal HSCs, and BMI1, PTEN, and CEBPA for adult HSCs). (A) During the neonatal period when the molecular driving force is balanced in fetal to adult hematopoiesis, healthy newborns can complete the transition from fetal to adult hematopoiesis to meet the needs for growth in normoxia. (B) When the molecular driving force is disrupted in newborns during the fetal-to-adult hematopoiesis switch by mutations or dysregulated epigenetics, fetal hematopoiesis is sustained and causes myeloid/lymphoid distribution errors and insufficient adult hematopoiesis in juveniles, resulting in pediatric demise. This may be the case in patients with JMML who are born with an NF1 mutation and hold an instable molecular driving force from fetal to adult hematopoiesis switch, such as elevated fetal-specific LIN28B and HMGA2 along with PTEN and BMI1 deficiencies. Because JMML patients cannot develop adult hematopoiesis at an age when WT juveniles normally complete their fetal-to-adult hematopoiesis switch, they die of sustained fetal hematopoiesis as juveniles.