JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival

Abstract

A common JAK2 germline haplotype (46/1) has been associated with JAK2V617F (VF)-positive myeloproliferative neoplasms. The rs12343867 SNP (C/T) tags this haplotype. A total of 130 patients (77 VF-positive) with primary myelofibrosis (PMF) were analyzed for this informative SNP, using bone marrow-derived DNA. The observed 46/1 C allele frequencies in VF-positive (50%) and VFnegative (36%) patients were both significantly higher than expected in population controls (Po0.01). Genotype distributions in VF-positive/VF-negative patients were CC 31%/9%, CT 38%/53% and TT 31%/38% (P ¼ 0.01). CC genotype/C-allele frequencies in patients with o20% VF mutation burden (12%/ 37%) were similar (P ¼ 0.95) to those seen in VF-negative patients (9%/36%), but were significantly lower (Po0.01) than those seen in the presence of 450% mutation burden (B67%/71%). The rs12343867 genotype did not correlate with the International Prognostic Scoring System (IPSS) score or karyotype. Unexpectedly, the TT genotype was associated with shortened survival (Po0.01), which was not accounted for by IPSS score or VF allele burden. We conclude that JAK2 germline genetic variation affects disease susceptibility, and possibly survival, in PMF, regardless of VF mutational status. Allelic distortion from acquired uniparental disomy contributes to the appearance of a more pronounced effect on disease susceptibility in VF-positive patients, when studying clonally affected tissue.

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

“…[2][3][4][5] We confirmed these observations in two recent papers 6,7 and also showed increased JAK2 46/1 haplotype frequency in VF-negative essential thrombocythemia (ET) 6 and primary myelofibrosis (PMF). 7 In the latter two studies, the JAK2 46/1 haplotype frequencies in both PMF (44%) and ET (41%) were significantly higher than that of the Wellcome Trust Case Control Consortium (WTCCC) (24%) or local (28%) control population, but similar in VF-positive versus VF-negative PMF (37 versus 36%) or ET (41 versus 38%), after adjusting for VF allele burden (that is, considering only patients with low allele burden to minimize allelic distortion from acquired uniparental disomy). A functional variant associated with the JAK2 46/1 haplotype could promote altered signaling and influence phenotype in the presence of VF or other JAK-STAT-relevant mutation, such as mutant MPL.…”

“…6 It could be demonstrated that the AML1-ETO fusion gene and FLT3 length mutations collaborate in inducing acute leukemia in mice and there is first evidence that the combination of AML1-ETO and JAK2 V617F mutations results in AML. 7,8 Recently, several studies have shown that in core-binding factor AML up to 40% of t(8;21) patients have additional mutations of the KIT gene, while the total incidence of c-KIT mutations in all AML is B5%. 9,10 Mutations of the NRAS gene have been reported in up to 10% of AML1-ETO cases, whereas other mutations in genes as AML1 and PU.1 occur only rarely in combination with t(8;21).…”

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…MPL and JAK2 mutation analyses were performed according to previously published methods. [26][27][28][29] IDH1 and IDH2 mutations were analyzed by direct sequencing and/or high-resolution melting assay. 30 Unfavorable karyotype designation 31 and International Prognostic Scoring System (IPSS), 32 DIPSS, 33 and DIPSSplus 21 21 Leukemic transformation risk was considered high in the presence of unfavorable karyotype or platelet count less than 100 ϫ 10 9 /L or low in the absence of both of these risk factors.…”

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

“…More recently, a number of DIPSS-plus-independent risk factors in PMF were identified and they include driver mutations other than type 1 or type 1-like CALR variants [44], monosomal karyotype [74], nullizygosity for JAK2 46/1 haplotype [75], low JAK2V617F allele burden [76,77], presence or number [78] of IDH1/2 [51], EZH2 [51], SRSF2 [51], or ASXL1 mutations [51], and increased serum IL-8 [79], IL-2R [79] or serum free light chain levels [80]. In a recent international study of 570 patients with PMF [81], the authors reported the longest …”