The JAK2 46/1 haplotype predisposes to MPL mutated myeloproliferative neoplasms

The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n=404) versus controls (n=1492; P=3.9x10(-11)). 46/1 was also overrepresented in cases without V617F (n=347, P=0.009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 non-mutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n=176, P=0.002) but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n=69, P=0.002) and these mutations preferentially arose on the 46/1 chromosome (P=0.029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 mutated cases is compatible with both the 'hypermutability' and 'fertile ground' hypotheses, but the excess in MPL mutated cases argues against the former. No difference in sequence, splicing or expression of JAK2 was found on 46/1 compared to other haplotypes suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle