Abstract 5173

It is predicted that the inherited genetic background in the individual patients with myeloproliferative neoplasm (MPN) influences the disease susceptibility and the phenotype expression of the MPN. Recently, several groups suggested that JAK2V617F positive MPN are acquired preferentially on a specific constitutional germline JAK2 46/1 haplotype which is tagged by the “C” allele of single nucleotide polymorphism (SNP) rs12343867 (C/T), and designate the genetic basis for predisposition to MPN. They try to explain the pathomechanism for the acquisition of V617F mutation trough the “hypermutability hypothesis” suggesting as a main mechanism the genomic instability at the JAK2 locus. But, subsequent data, showed equal distribution of this SNP among JAK2V617F negative MPN, indicating that it is a potential common inherited susceptibility factor for MPN. Moreover, only few studies investigated the potential role of the JAK2 46/1 haplotype at the MPN phenotype in context of the clinical presentation and the complication of the diseases.

In order to extend further those observations we conduct a retrospective study. First, we assess the frequency of JAK2 46/1 haplotype in a group of patients with MPN in comparison with population controls.

As second we evaluate the association of 46/1 with the JAK2V617F mutational status and the clinical characteristics in the series of patients with different entities of MPN that were diagnosed and treated at the University Clinic of hematology-Skopje, Republic of Macedonia.

The study group consisted of 212 adult (>15 years) patients with MPNs that were diagnosed and followed at the University Clinic of Hematology- Skopje. According to the 2008 World Health Organization criteria 79 patients were diagnosed as Polycythemia vera (PRV), 95 as Essential thrombocythemia (ET), 10 as Myelofibrosis primaria (MF) and 28 were classified as atypical MPN (aMPN).

The 46/1 tag SNP rs12343867 (C/T) was genotyped using the TaqMan SNP genotyping assay (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. The JAK2 V617F mutation was analyzed by fluorescent allele-specific PCR followed by CE on ABI 310 Genetic analyzer.

The incidence of 46/1-linked C allele was significantly higher in all MPN entities [PRV (0.538), ET (0.437), MF (0,464), and in aMPN (0.55)] in comparison with healthy controls (0.290); (P<0,01 for all comparisons).

The frequency of the JAK2V617F mutation ranged from 89%in PRV, 67% in ET, 60% in MF to 46,4% in the aMPN. The frequency of the JAK246/1 C allele was significantly higher in the JAK2V617F positive patients with PRV, MF and aMPN; (p<0,01 for all comparisons) except in ET patients, in which genotype distributions were similar among JAK2V617F positive and JAK2V617F negative patients (genotype: CC 7/14%, CT 22/29%, TT 67/57%; C-allele frequency 41/43%; p=0,76)

Correlations of the clinical features at diagnosis and long-term prognosis between the two JAK2 46/1 different MPNs groups revealed comparability regarding all tested parameters such as blood counts, NAP score, rate of thrombotic and hemorrhagic complications, disease transformation and survival

Our results confirmed latest observations that JAK2 46/1 haplotype is a susceptibility factor for developing ET independent of JAK2V617F mutational status. They also showed that the JAK2 46/1 haplotype does not affect the clinical course and prognosis of the different entities of MPN neoplasm. Our findings indicate that JAK2 46/1 haplotype predispose for development of MPN trough “the fertile ground hypothesis” which suggest that cells that are carrying the haplotype gain selective advantages in situations when oncogenic mutations occur.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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