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The JAK2 V617F Mutation in Pediatric Myeloproliferative Neoplasms: How and When?

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are uncommon in children with an incidence estimated at approximately forty to ninety fold lower than that seen in adults [1]. Pediatric MPN patients exhibit a significantly lower prevalence of the JAK2 V617F mutation, which in both PV and ET, increases with age through adolescence into adulthood and old age [2–4]. Furthermore, pediatric MPN patients have a lower JAK2 V617F allele burden than that observed in adults [5]. These observations emphasize the differences in both the etiology and pathogenesis of childhood MPN when compared to the adult diseases and imply that an increasing degree of genomic instability related to progressing age is a contributory factor in facilitating the acquisition of the JAK2 V617F and subsequent development of clinically overt MPN. The accumulation of a number of possible mutational events over time in adult MPN patients associated with either disease progression, myelofibrotic, or leukemic transformation argues that expression of the mutant JAK2 protein itself promotes defective DNA damage repair; this has been confirmed by both in vivo and in vitro observations [6]. There is also some evidence to suggest that an intrinsic genomic instability pre-exists in the hematopoietic stem cells of adult MPN patients prior to the acquisition of the JAK2 V617F mutation [6]. Somewhat conversely, a prenatal origin of the JAK2 V617F mutation has been demonstrated in an infant with PV and more recently in a case of childhood ET [7, 8]. Demonstration of the mutation in the peripheral blood at birth in these instances supports the hypothesis that acquisition of the JAK2 V617F occurs early in fetal hematopoietic development with expansion of this clone occurring in tandem with normal hematopoiesis to a level that is detectable by allele-specific PCR in antenatal blood spots. This apparent dichotomy regarding when the JAK2 V617F mutation is acquired could possibly be related to age of presentation: younger patients with a molecular, prenatal origin might have an MPN that is phenotypically and genotypically distinct from the disease in older children and adolescents which clinically resembles