The myeloproliferative neoplasm-associated JAK2 46/1 haplotype is not overrepresented in chronic myelogenous leukemia

Abstract

Dear Editor, Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis [1]. In 2005, a point mutation in JAK2 (JAK2V617F) was shown to occur in almost all patients with PV and in ≈60% of ET or PMF [2]. A genetic predisposition to developing MPNs has been long suggested by finding clusters of MPNs in kindreds as well as by recent results of a large registry-based epidemiological study performed in Sweden. In this analysis, almost 25,000 relatives of 11,039 patients with MPNs were evaluated. There was a significantly increased relative risk (RR) of developing MPN among first-degree relatives in the order of 5.7, 7.4, and 7.5 for PV, ET, and not otherwise specified MPN, respectively, compatible with a model of autosomal recessive inheritance [2]. While an increased RR for PMF could not be demonstrated, possibly because of the relatively low number of cases observed, an almost statistically significantly higher RR of developing Ph’-positive chronic myelogenous leukemia (CML) was found (RR 1.9, 95% confidence interval 0.9–3.8, P=0.09). Recently, the genetic basis for predisposition to MPNs has been partially clarified by the discovery that the JAK2V617F mutation is acquired preferentially on a specific constitutional JAK2 haplotype. This haplotype, which is called 46/1 or GGCC, is a common, very low penetrance predisposition allele estimated to account for 50% of the population-attributable risk of developing a MPN. In three independent studies, 46/1 has been identified as a germline haplotype block that is strongly associated (3 to 4 odds ratio) with JAK2V617Fmutated MPN [3–5]. Subsequent studies showed association of this haplotype also with JAK2 exon 12-mutated PV [6], JAK2-wild type ET [7], and MPLW515-mutated PMF or ET [8], suggesting that the haplotype increases the risk of developing an MPN regardless of the acquisition of the V617F mutation. However, in another recent study, no such association with MPL mutations was reported [9]. We therefore asked whether the increased risk of developing CML in MPN relatives found in the epidemiological study could be similarly attributed to an increased prevalence of the 46/1 haplotype compared with control subjects. This study reports on two different patients series with Ph’-positive CML collected in Florence (Italy) and in Mannheim (Germany) and analyzed independently using two 46/1 tag SNPs. In the Italian series, the 46/1 tag rs12343867 (with the “C” allele standing for 46/1 haplotype) was analyzed by allelic discrimination using Applied Biosystems SNP genotyping assay; in the German series, the rs12340895 SNP (with “G” allele standing for 46/1 haplotype) was analyzed in Salisbury laboratory by pyrosequencing as described [3]. As control populations, we used 235 healthy volunteers living in Florence for the A. Spolverini : L. Pieri :A. M. Vannucchi (*) UF di Ematologia, Dipartimento di Area Critica Medico-Chirurgica, Universita di Firenze, Istituto Toscano Tumori, Florence, Italy e-mail: amvannucchi@unifi.it