Does JAK2 1849G>T initiate polycythemia vera?

Comment on Bellanné-Chantelot et al, page 346

In this issue of Blood, Bellanné-Chantelot and colleagues report on a remarkable and likely unparalleled collection of 72 families with 174 relatives who have myeloproliferative disorders.

The familial clustering of sporadic disorders of acquired clonal hematopoietic disorders is indeed rare.¹  This clinical gold mine, which has taken decades and a cadre of academic hematologists in France and Belgium to accumulate, was subjected to molecular studies searching for the presence or absence of JAK2 1849G>T mutation. Multiple papers within a short period of time have reported on a somatic mutation in the autoinhibitory domain of JAK-2 present in the vast majority of polycythemia vera cases (reviewed in Emanuel and Prchal² ). When the proportion of mutant JAK2 was enumerated, it was seen in either a minority and interpreted as a heterozygous mutation or in a majority and then interpreted as a homozygous mutation. This heterogeneity of mutation dose was previously shown to be generated by a process of uniparenteral disomy.³  Of importance, this mutation was shown to emulate the in vitro behavior of native polycythemia vera cells, such as erythropoietin independence of erythroid growth, and when introduced into mouse stem cells (only as a mutant transgene, ie, akin to “homozygous mutation”) resulted in development of polycythemia and subsequently myelofibrosis.⁴  Additionally, the JAK2 1849G>T mutation was seen, albeit less often, in other myeloproliferative disorders and in patients with other clonal blood malignancies. This has raised the question of whether this is indeed the polycythemia vera-causing mutation. Of the 174 affected relatives in this French/Belgian study, 81 had polycythemia vera; 68, essential thrombocythemia; 11, myelofibrosis; and 12, chronic myeloid leukemia. About three quarters of polycythemia vera patients, and a significant proportion of the primary myelofibrosis and essential thrombocythemia patients, also had JAK2 1849G>T mutation. The prevalence of the JAK2 1849G>T mutation in these familial polycythemia vera patients was less than that seen in sporadic polycythemia vera by others.² 

This convincing study of Bellanné-Chantelot and colleagues clearly points out that JAK2 1849G>T is not the disease-causing mutation; after all, the mutation in this large study was found only in myeloid progenitors and not in the germ line, and in some families, only some of the affected relatives had the JAK2 mutation. This contention is supported by other accumulating observations. First, if only one allele of JAK2 is mutated, then 50% of JAK2 should be JAK2 1849G>T; if both alleles are mutated, then 100% should be JAK2 1849G>T. However, careful quantitative studies of the proportion of JAK2 1849G>T mutation reveal that the mutant is less than 50%, more than 50%, and generally less than 100% in clonal polycythemia vera granulocytes, while 0%, 50%, or 100% proportions are seen in cells from single polycythemia vera erythroid burst-forming unit (BFU-E) colonies. Second, studies of clonogenic polycythemia vera erythroid BFU-Es show that those that are erythropoietin-independent are mainly those that contain approximately 100% of mutant Jak2 (regardless of the proportion of JAK2 mutant in clonal granulocytes) but occasional colonies are also 50% mutant JAK2 (J.P., unpublished data, 2006).

Clearly, this paper will serve as an invaluable resource to identify the polycythemia vera-initiating mutation(s) and may eventually elucidate why a single nucleotide mutation is a recurrent theme in so many acquired somatic mutations that constitute phenotypes of myeloproliferative and other clonal hematopoietic disorders. ▪