JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms

Abstract

Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation1–4. We report here that JAK2V617F-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 × 10−16; essential thrombocythemia, n = 78, P = 8.2 × 10−9 and myelofibrosis, n = 41, P = 8.0 × 10−5). Furthermore, JAK2V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2V617F-associated MPNs (OR = 3.7; 95% CI = 3.1–4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.

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).…”

“…JAK2 46/1 haplotype allele frequencies in the study population were compared with those of population (WTCCC; n ¼ 1500) and local (n ¼ 57) controls. 2 For the current study, MPL mutation analysis was performed in 161 consecutive VF-negative patients (median age 55 years; 82 females) with ET (n ¼ 108) or PMF (n ¼ 53). Of these, 12 (B8%) displayed either MPLW515L or MPLW515K, including 6 (6%) of the 108 patients with ET and 6 (B11%) of the 53 patients with PMF.…”

“…1 One such translocation, t(8;21)(q22;q22) generating the fusion protein AML1-ETO, is found in up to 15% of AML patients. 2 This fusion protein consists of the N terminus of AML1 and nearly the entire ETO protein with its four Nervy homology regions (NHRs) (Figure 1). The DNA-binding Runt domain of AML1 is believed to be crucial for leukemogenic activity of AML1-ETO and while only little is known about the contribution of NHR3 to malignant transformation, NHR1 and NHR2 (mediating oligomerization with AML1-ETO) seem to be essential in inhibiting cell proliferation and differentiation.…”

Frequency and clinical correlates of JAK2 46/1 (GGCC) haplotype in primary myelofibrosis

“…[9][10][11] Subsequent studies also showed significant association of this haplotype, with JAK2 exon 12-mutated, 12 JAK2-wild type ET, 13 and MPLW515-mutated PMF or ET, 14 suggesting that this haplotype increases the risk of developing a MPN, regardless of the acquisition of the V617F mutation. However, in another recent study, no such association with MPL mutations was described.…”

JAK2 GGCC haplotype in MPL mutated myeloproliferative neoplasms

“…The JAK2 (V617F) mutation, found in about two thirds of patients with a myeloproliferative neoplasm (MPN), is preferentially detected in subjects with a common constitutional JAK2 haplotype known as 46/1 or GGCC [1][2][3]. The mechanism underlying this predisposition has not been elucidated so far.…”