The amount of JAK2 617V>F matters

In this issue of Blood, 2 notable papers address the importance of the absolute amount of, and/or homozygosity versus heterozygosity for, the somatic mutation JAK2 617V>F in polycythemia vera (PV) and essential thrombocythemia (ET). The relationship of the level of JAK2 617V>F with the cell biology of these disorders and with clinical complications and laboratory parameters is critically evaluated.

Dupont and colleagues confirm and extend the work of others, which has demonstrated that most patients with ET (but, as they show, not all), have a lower proportion of JAK2 617V>F compared with PV patients, and this somatic mutation is generally present in ET in heterozygous forms. Patients with PV have a much higher proportion of JAK2 617V>F in circulating granulocytes, wherein the level of this mutation closely parallels that present in the bone marrow. Most PV patients have at least some progenitors homozygous for this mutation, which coexist with heterozygous and wild-type JAK 2 progenitors. In contrast to previous reports, they clearly delineate a subgroup of PV patients who are not homozygous for this mutation, showing instead that in this group, virtually all erythroid progenitors bear a single copy of this mutation. The experimental conditions used by the authors allow them to conclude that erythroid progenitors bearing the mutant JAK2 617V>F gene have an in vitro proliferative advantage to those bearing the wild-type JAK2 gene. They correlate their findings with the clinical phenotype of PV and ET patients and demonstrate that the higher the level of mutant JAK2 617V>F, the higher the absolute granulocyte count, the greater the proportion of erythropoietin-independent colonies, and, unexpectedly, the lower the platelet count; relatively low levels of JAK2 617V>F mutation are associated with thrombocytosis.

In another article focusing upon JAK2 617V>F, Vannucchi and colleagues, using a large number of patients (967), correlated clinical and laboratory parameters with the proportion of JAK2 617V>F mutation. Unlike Dupont and colleagues, these investigators did not always quantify the proportion of mutant JAK2, but analyzed the patients based on homozygosity, heterozygosity, and the absence of the mutation. They confirmed the association of homozygosity (higher level of mutant) with elevated leukocyte count but also with the presence of splenomegaly, greater size of spleen, pruritus, and a greater likelihood of transformation to myelofibrosis. Compared with Dupont's study, this paper reports a slightly greater proportion of homozygous JAK2 617V>F patients in the ET group, and this subgroup had significantly more thrombotic complications than other ET patients. Both homozygous ET and homozygous PV patients were also more likely to be treated with chemotherapy (determined prior to knowledge of JAK2 mutational status).

These 2 papers contribute to the growing evidence of the importance of the absolute level of JAK2 617V>F in differential diagnosis and prognosis. However, while the large retrospective analysis conducted by Vanucchi' s group examined homozygous versus heterozygous status of JAK2 617V>F, it remains to be established that the same clinical correlation will exist when only the absolute level of JAK2 617V>F, separate from zygosity, is studied. Thus, prospective studies correlating clinical and laboratory features with the absolute proportion of JAK2 617V>F in clonal cells, such as granulocytes, will be needed. Assays to detect absolute JAK2 617V>F levels already exist and are becoming commercially available.¹ 

Data collected by Dupont and colleagues also support the conclusions reached by others^1,2  that the JAK2 617V>F mutation is not a disease-initiating mutation, but rather a second hit. This has significant therapeutic importance, since it is likely that the JAK2 inhibitors currently under development would not eliminate the PV and ET clones but may eliminate or ameliorate some PV complications. The unexpected observation that PV transformed to acute leukemia is, in most instances, JAK2 617V>F negative (Jelinek et al³  and other subsequent reports) suggests that this universally fatal PV and ET complication may not be prevented by JAK2 inhibitors. While the article by Dupont and colleagues suggests that JAK2 617V>F–positive PV cells have an advantage at normal or increased erythropoietin concentrations in vitro, this differs diametrically with other reports using different conditions that showed the JAK2 617V>F cells are, in fact, at a disadvantage compared with JAK2 617V>F–negative cells when grown with high erythropoietin concentrations.^4,5  If the latter is true, then erythropoietin supplementation in conjunction with other therapies may contribute to restoration of normal hematopoiesis.