Original Article

Leukemia (2010) 24, 105–109; doi:10.1038/leu.2009.225; published online 22 October 2009

Chronic Myeloproliferative Neoplasias

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

A Tefferi1, T L Lasho1, M M Patnaik1, C M Finke1, K Hussein1, W J Hogan1, M A Elliott1, M R Litzow1, C A Hanson2 and A Pardanani1

  1. 1Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
  2. 2Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

Correspondence: Professor A Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: tefferi.ayalew@mayo.edu

Received 11 September 2009; Accepted 22 September 2009; Published online 22 October 2009.



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 VF-negative (36%) patients were both significantly higher than expected in population controls (P<0.01). Genotype distributions in VF-positive/VF-negative patients were CC 31%/9%, CT 38%/53% and TT 31%/38% (P=0.01). CC genotype/C-allele frequencies in patients with <20% VF mutation burden (12%/37%) were similar (P=0.95) to those seen in VF-negative patients (9%/36%), but were significantly lower (P<0.01) than those seen in the presence of >50% mutation burden (~67%/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 (P<0.01), 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.


JAK2, V617F, haplotype, SNP, myelofibrosis, prognosis



The association of a JAK2 mutation (JAK2V617F (VF)) with BCR-ABL-negative, classic myeloproliferative neoplasms (MPNs) is one of the most seminal medical discoveries in recent years.1 VF is detected in approximately 97, 60 and 60% of patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), respectively.2 The mutation also occurs, albeit less frequently, in other MPNs (for example, chronic neutrophilic leukemia) and in patients showing the features of both MPN and myelodysplastic syndromes (for example, refractory anemia with ring sideroblasts and marked thrombocytosis).3, 4 Mutational frequency is <5% in myelodysplastic syndromes or de novo acute myeloid leukemia.5 VF is rarely encountered in patients with lymphoid malignancies or solid tumor.6

VF is a major component of the PV phenotype, induces PV-like disease in mice, originates at the stem cell level and involves both myeloid and lymphoid lineage cells.7 However, since its initial description, additional JAK28, 9 and non-JAK210, 11, 12, 13, 14 mutations have been described in PV and related MPN. Furthermore, several lines of evidence suggest that VF is neither the initial clonogenic event nor a pre-requisite for MPN progression into acute leukemia, and instead might be one of several sub-clones derived from an ancestral clone the identity of which is currently not known.15, 16, 17, 18 A characteristic feature of VF is mitotic recombination of chromosome 9p that accompanies the mutation and reduces it, and any SNP allele that is in linkage disequilibrium with the mutation, to a homozygous state.19 Why this acquired uniparental disomy occurs in PV and PMF but not as frequently in ET is not clearly understood.20 Regardless, VF allele burden might have a role in specifying the disease phenotype, as has been shown in relevant murine models.21, 22

Early on, we hypothesized a contributory role from both other disease alleles and germline genetic variations as an explanation for the association of VF with more than one MPN phenotype. We subsequently demonstrated the coexistence of a dominant MPLW515K/L clone with a minor VF clone in some patients with PMF23 and also an association between specific JAK2 SNP alleles and PV/ET.24 More recently, three independent groups reported an association between a specific JAK2 haplotype, which some designated as 46/1, and VF-positive MPN.25, 26, 27 This particular phenomenon has also been demonstrated in the setting of JAK2 exon 12 mutations.28 In this study, we sought to clarify the impact of JAK2 germline genetic variation on (i) disease susceptibility in both VF-positive and VF-negative PMF, and (ii) the clinical characteristics and prognosis in PMF.


Materials and methods

The Mayo Clinic database of adult PMF patients (age greater than or equal to18 years) was utilized to select consecutive patients seen from 1980 onwards and in whom stored bone marrow (BM) cells were available for DNA extraction. Permission was obtained from the institutional review board to examine the medical records of all study patients and perform the below-stipulated molecular studies. Follow-up information was updated in July–August 2009. Diagnosis of PMF was made according to the World Health Organization (WHO) criteria after a re-review of both clinical information and BM histology in all cases.29 Special care was undertaken to avoid inadvertent inclusion of patients with myelodysplastic syndrome associated with BM fibrosis. For the purposes of this study, the diagnosis of acute myeloid leukemia required the presence of greater than or equal to20% blasts in the BM.30 Quantitative analysis of VF was performed using BM-derived cells, according to previously published methods.31 In order to screen for the JAK2 46/1 haplotype, we genotyped rs12343867 SNP, which is in complete linkage disequilibrium with the 46/1 haplotype,25 using a commercially available TaqMan SNP genotyping assay (Applied Biosystems Inc., Foster City, CA, USA). The International Prognostic Scoring System (IPSS) was applied for clinical staging.32 Cytogenetic risk assignment was done according to recently published information.33, 34, 35

Descriptive and statistically analyzed data were based on parameters collected at the time of initial diagnosis. JAK2 46/1 haplotype allele frequencies in the study population (n=130) were compared with those of population controls (n=1500) from the Wellcome Trust Case Control Consortium, using χ2 statistics.25 Statistical procedures utilized were conventional and all data were analyzed by using StatView (SAS Institute, Cary, NC, USA). All P-values were two-tailed and statistical significance was set at the level of P<0.05. Continuous variables were summarized as medians and ranges. Categorical variables were described as count and relative frequency. Comparison between categorical variables was performed using χ2 statistics. Comparison between categorical and continuous variables was performed using either the Mann–Whitney U test or Kruskal–Wallis test. Survival analysis was performed using the Kaplan–Meier method, taking the interval from the date of diagnosis to death, time of allogeneic hematopoietic cell transplantation or last contact. The log-rank test was used to compare survival data. The Cox regression model was used for multivariable analysis.



A cohort of 130 patients (median age 62 years; 82 men) with WHO-defined PMF was studied. Their clinical and laboratory details are outlined in Table 1. Risk distribution according to the IPSS for PMF was low in 39 (30%) patients, intermediate-1 in 39 (30%), intermediate-2 in 25 (19%) and high in 27 (21%); Figure 1 shows the IPSS-stratified survival data (P<0.01), which confirms the representative nature of the study population. Seventy-seven (59%) patients were VF positive. Among mutation-positive patients, the median mutant allele burden was 26% (range 1–85); 26, 30 and 21 patients displayed <20%, 20–50% or >50% mutant allele burden, respectively. Consistent with our previous observations, VF-positive patients, compared with mutation-negative patients, were significantly older (P=0.004)36 and the presence of the mutation did not carry an age-independent effect on prognosis.36 Also consistent with the results from two recent studies,31, 37 there was a trend for shorter survival in patients with <50% VF allele burden compared with those with either higher allele burden, or they were mutation-negative (P=0.08). Karyotype at diagnosis was available for 91 patients and the findings were abnormal in 38 (42%).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Survival in 130 patients with primary myelofibrosis stratified according to the International Prognostic Scoring System (IPSS).32

Full figure and legend (67K)

The rs12343867 SNP genotype distribution in the 130 study patients, CC 22% (n=29), CT 44% (n=57) and TT 34% (n=44), was significantly different from those of both local (n=57; 7%, 42%, 51%, respectively; P=0.02) and HapMap (Northern/Western European ancestry) listed (6, 46 and 48%, respectively; P<0.01) controls. The corresponding genotypes in VF-positive/VF-negative patients were CC 31%/9%, CT 38%/53% and TT 31%/38% (P=0.01). The JAK2 46/1 haplotype frequencies (that is, the rs12343867 C-allele frequency) of 44% (entire cohort; n=130), 50% (VF-positive cases; n=77) and 36% (VF-negative cases; n=55) of the patients were all significantly higher than those of the population controls from the Wellcome Trust Case Control Consortium (24%; P<0.01). In VF-positive patients, the CC genotype frequency was 67% in the presence of >50% mutant allele burden and 12% when the allele burden was <20% (P<0.01). In order to clarify the contribution of acquired uniparental disomy to JAK2 haplotype allele frequency, patients with <20% VF allele burden (n=26) were analyzed separately and were found to show CC, CT and TT genotype distribution (12%, 50%, 38%), and C-allele frequency (37%) that were similar to those seen in VF-negative patients: 9%, 53% and 38%, and 36%, respectively (P=0.94) (Table 2).

Table 1 outlines the clinical and laboratory parameters of the study patients stratified by their SNP genotype, which was not significantly affected by age (P=0.40), sex (P=0.39) or prognosis-relevant clinical parameters, including hemoglobin level (P=0.83), leukocyte count (P=0.29), platelet count (P=0.12), cytogenetic findings (P=0.74) or IPSS risk category (P=0.61). The only significant association noted was, as elaborated in the above paragraph, with VF mutational status (P=0.01) and allele burden (P<0.01).

Patients were followed for a median of 54 months (range 0.5–274), and during this period 76 (59%) deaths, 15 (12%) leukemic transformations, 25 (15%) splenectomies and 107 (81%) therapeutic interventions were documented. Only four patients were documented to have undergone allogeneic hematopoietic cell transplantation and were censored at the date of their transplant during survival analysis. The rs12343867 SNP genotype did not correlate with the need for either splenectomy (P=0.32) or specific therapy (P=0.48). Unexpectedly, homozygosity for the non-46/1 JAK2 haplotype (that is, TT) was significantly associated with shortened survival (P<0.01; Figure 2). Multivariable analysis showed this association to be independent of IPSS, VF mutational status or allele burden, age or sex. The adverse prognostic effect of the TT genotype was most apparent in VF negative (Figure 3; P=0.02) as opposed to mutation-positive (P=0.07) cases.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Survival in 130 patients with primary myelofibrosis stratified according to the JAK2 46/1 haplotype single-nucleotide polymorphism (SNP) genotype (rs12343867).

Full figure and legend (59K)

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Survival in 53 JAK2V617F-negative patients with primary myelofibrosis stratified according to the JAK2 46/1 haplotype single-nucleotide polymorphism (SNP) genotype (rs12343867).

Full figure and legend (45K)



Using a large representative cohort of patients with PMF (n=130), we show that the JAK2 46/1 haplotype is enriched in both VF-positive and VF-negative cases; the respective haplotype allele frequencies of 50 and 36% were both significantly higher than the ~24% expected in the Wellcome Trust Case Control Consortium control population. Similarly, increased JAK2 haplotype allele frequencies were reported by Jones et al.25 in VF-positive PMF (48%; n=41) and VF-negative PMF or ET (38%; n=47). In this study, we were able to clarify the confounding effect of VF allele burden by demonstrating, first, its direct correlation with JAK2 haplotype allele frequency and, second, the almost identical rs12343867 genotype distribution between VF-negative (9% CC, 53% CT, 38% TT) and VF-positive patients with <20% mutation burden (12% CC, 50% CT, 38% TT). The latter patient population was considered in order to minimize allelic distortion from acquired uniparental disomy, as we used clonally affected tissue for 46/1 screening.

Based on the above-mentioned observations, it is reasonable to surmise that acquired uniparental disomy contributes to the appearance of a stronger association between PMF and the JAK2 haplotype in the presence of VF. In support of this contention, and in contrast to the observations from another two related studies,27, 28 we also found that VF-negative and VF-positive cases, among 226 ET patients seen at our institution, were both similarly enriched for 46/1 (see the accompanying article by Pardanani et al). One could argue that an even larger study might reveal a significant but small difference between VF-positive and VF-negative cases regardless of VF allele burden. However, it is difficult, in that context, to be certain that all VF-negative cases represent the specific phenotype that is being considered. In other words, in the absence of an objective clonal marker, it is possible to inadvertently include inaccurately diagnosed cases that could water down the association between 46/1 and VF-negative MPN. Taken together, it is reasonable to conclude that JAK2 genetic variation increases susceptibility to the disease, and not only to the acquisition of VF, in PMF.

Several possibilities have been put forth to account for the association between 46/1 and VF-positive MPN. One hypothesis considers 46/1 as being more mutation-prone compared with other JAK2 haplotypes.25, 26 This would be consistent with the recent report by Olcaydu et al.28 on the association of 46/1 with other JAK2 mutations in MPN. Another hypothesis entertains the presence of a functional variant in the 46/1 haplotype that promotes either the acquisition of JAK2 mutations27 or the development of disease once the mutation has occurred.25, 26 However, the results of this study suggest that the association between 46/1 and MPN might not be tied to a specific mutation but to a clinicopathologic phenotype that is also known to be associated with non-JAK2 mutations. Considering the fact that the latter might also use JAK-STAT as their main signaling route, it is still possible for a functional variant within 46/1 to contribute to phenotypic specification by influencing a common constitutive signal pathway rather than a specific mutation. Alternatively, within the repertoire of non-46/1 haplotypes, some might be defective in terms of supporting clonal proliferation, thus forcing preponderance of 46/1 in the population with disease.

An unexpected finding in the current study was the association between nullizygosity for the JAK2 46/1 haplotype SNP allele (that is, rs12343867 TT genotype) and shortened survival, which could not be accounted for by other conventional prognostic parameters such as IPSS or karyotype. The particular SNP genotype groups were otherwise similar in their age and sex distribution and their clinical and laboratory characteristics, as illustrated in Table 1. A potential explanation for this intriguing phenomenon requires the understanding that PMF is probably not one disease but a molecularly heterogeneous group of diseases that share similar blood and BM changes. Therefore, if one were to endorse the possibility that 46/1 selects for VF-associated (or similarly behaving) disease, it is equally possible that non-46/1 haplotypes are affiliated more with a biologically more aggressive phenotype. Consistent with this contention, the survival effect of the TT SNP genotype was more evident in VF-negative patients. In this regard, it is important to distinguish this putative mechanism from that considered responsible for the inferior survival of PMF patients with low VF allele burden;31, 37 in the latter scenario, we had proposed that low VF allele burden was a surrogate for the presence of an overriding VF-negative clone that confers a more aggressive disease phenotype.31 Regardless, more studies with larger number of patients, additional information on causes of death and transformation, and examination of response patterns during anti-JAK2 therapy38, 39, 40 are needed to confirm these observations and obtain further insight.


Conflict of interest

The authors declare no conflict of interest.



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