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Jones, A.V.* ; Campbell, P.J.* ; Beer, P.A.* ; Schnittger, S.* ; Vannucchi, A.M.* ; Zoi, K.* ; Percy, M.J.* ; McMullin, M.F.* ; Scott, L.M.* ; Tapper, W.* ; Silver, R.T.* ; Oscier, D.* ; Harrison, C.N.* ; Grallert, H. ; Kisialiou, A.* ; Strike, P.* ; Chase, A.J.* ; Green, A.R.* ; Cross, N.C.P.*

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

Blood 115, 4517-4523 (2010)
Open Access Green as soon as Postprint is submitted to ZB.
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 = 3.9 x 10(-11)). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .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 = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .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 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 with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Familial polycythemia-vera; Genome-wide association; Essential thrombocythemia; Confers susceptibility; Crohns-disease; Disorders; Mutations; Myelofibrosis; Heterogeneity; Pathogenesis
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 115, Issue: 22, Pages: 4517-4523 Article Number: , Supplement: ,
Publisher American Society of Hematology
Reviewing status Peer reviewed