MPL mutation effect on JAK2 46/1 haplotype frequency in JAK2V617F-negative myeloproliferative neoplasms

摘要

Consistent with an earlier suggestion of linkage disequilibriumbetween certain JAK2 haplotypes and polycythemia vera,1 threeindependent groups recently reported an association betweena specific JAK2 haplotype, designated as 46/1, and JAK2V617F(VF)- or JAK2 exon 12 mutation-positive myeloproliferativeneoplasms (MPNs).2–5 We confirmed these observations in tworecent papers6,7 and also showed increased JAK2 46/1 haplotypefrequency in VF-negative essential thrombocythemia (ET)6 andprimary myelofibrosis (PMF).7 In the latter two studies, the JAK246/1 haplotype frequencies in both PMF (44%) and ET (41%)were significantly higher than that of the Wellcome Trust CaseControl Consortium (WTCCC) (24%) or local (28%) controlpopulation, but similar in VF-positive versus VF-negative PMF (37versus 36%) or ET (41 versus 38%), after adjusting for VF alleleburden (that is, considering only patients with low allele burdento minimize allelic distortion from acquired uniparental disomy).A functional variant associated with the JAK2 46/1 haplotypecould promote altered signaling and influence phenotype in thepresence of VF or other JAK-STAT-relevant mutation, such asmutant MPL. Therefore, it is reasonable to consider the possibilitythat the increased JAK2 46/1 haplotype frequency seen inVF-negative MPN is attributed to the presence of a MPL mutation.The current study tests this hypothesis and also examines JAK246/1 haplotype frequency in MPL-mutated MPN.