JAK2^V617F and phenotype: questions galore

The JAK2^V617F mutation is associated with a range of hematologic disorders. Xu and colleagues find a surprisingly high prevalence of JAK2^V617F in a large cohort of unselected patients.

JAK2^V617F shows a near-invariable association with polycythemia vera (PV), and frequent association with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but is infrequently associated with “atypical” myeloproliferative disorders, myelodysplastic syndrome (MDS), or de novo acute myeloid leukemia. Recent studies also suggest frequent occurrence of this mutation in refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), and in patients with Budd-Chiari syndrome. JAK2^V617F incidence may vary between studies, reflecting the patient population studied, the biologic sample analyzed, and sensitivity of the molecular assay used for mutation screening.

The increasingly wider availability of JAK2^V617F assays and their use in newer clinical settings suggests that the phenotypic limits of the mutation have not yet been defined. Indeed, use of allele-specific polymerase chain reaction (AS-PCR) for JAK2^V617F detection where the assay sensitivity approaches 0.01% has recently identified a very low mutation level in the blood of up to 10% of healthy volunteers in one study.¹  In this issue of Blood, Xu and colleagues report a relatively high JAK2^V617F prevalence (approximately 1%) using AS-PCR (sensitivity limit of 0.25%) in their analysis of 3935 blood samples collected at a single Chinese hospital over 6 months. Both studies reveal a surprisingly high frequency of JAK2^V617F than would be predicted from estimates of myeloproliferative disorder (MPD) prevalence in the respective populations studied.

These findings are intriguing, yet confounding, and raise many questions regarding the phenotypic correlates of JAK2^V617F: first, can the findings be extrapolated to other populations? Indeed not as of now, it seems, given the failure to detect JAK2^V617F in healthy controls screened by comparably sensitive assays in other studies.²  Also, the specific population to which the current findings of Xu and colleagues is applicable is difficult to ascertain given the paucity of clinical data provided for their JAK2^V617F-positive patients. In considering patient blood counts, while nearly a third exhibited some degree of leukocytosis and/or thrombocytosis, these findings may be secondary or reactive, as would be commonly expected in a hospital population, and consequently, this cannot be taken as unequivocal evidence for early-stage MPD. Second, is acquisition of JAK2^V617F sufficient per se for MPD development? While these findings, if confirmed, suggest that JAK2^V617F is an early genetic event, they do not directly address this question. Expression of a particular MPD phenotype (say, PV) reflects time-dependent events, including progressive JAK2^V617F clonal dominance, accompanied in some cases by transition from JAK2^V617F heterozygosity to homozygosity through mitotic recombination,³  and potential acquisition of additional genetic “hits” (eg, JAK2^D620E or MPL^W515L/K)⁴  that may bias clinical disease expression. Last, does detection of JAK2^V617F by highly sensitive molecular assays indicate a “form fruste” of MPD in certain situations (eg, idiopathic thrombosis) where accepted diagnostic criteria for MPD are not fulfilled? While presently unknown, this is likely to be an area of intense interest that examines the contributions of JAK2^V617F gene dosage, zygosity, and clonal burden, as well as their interactions with other genetic and/or environmental factors (eg, inherited thrombophilias) toward expression of a particular clinical phenotype.