Homozygosity of germ line JAK2 46/1 haplotype contributes to phenotype and outcome diversity in polycythemia vera

The JAK2 V617F mutation is the most common driver mutation in myeloproliferative neoplasms (MPN), followed by mutations in CALR, MPL, and JAK2 exon 12.1 Although MPN are typically sporadic, ~25% of cases are associated with the low-penetrance germ line haplotype JAK2 46/1 (GGCC),2,3 with additional susceptibility loci reported in MECOM, TERT, and MYB. 4 The 46/1 haplotype is typically defined by up to 4 single nucleotide polymorphisms (SNPs) in complete linkage disequilibrium across a 250–kilobase pair region on 9p24.1, encompassing JAK2, INSL4, and INLS6. 3,5,6 It accounts for 70% to 80% of JAK2 V617F alleles,5,7-10 whereas its association with JAK2 wild-type MPN is less consistent.5,9,11 The haplotype has been linked to higher JAK2V617F mutation burden (or variant allele frequency [VAF])12 and its nullizigosity to reduced survival in myelofibrosis (MF).13 This study evaluates the phenotypic correlates and prognostic impact of the 46/1 haplotype in a large cohort of patients with polycythemia vera (PV).