T784C LNK gene polymorphism and the risk of myeloproliferative disorders.

The lymphocyte adaptor protein (LNK or SH2B3) negatively modulates the signaling through some cytokine receptors including receptors for thrombopoietin and erythropoietin by inhibition of the JAK2 kinase activation. A variety of LNK gene somatic mutations with weakening its inhibitory action leads to the myeloid proliferation which was manifested as thrombocytosis and erythrocytosis [1,2]. The association between the LNK gene single-nucleotide polymorphism (SNP) rs3184504 (c.784T.C) and the development of the Ph-negative myeloproliferative neoplasms (MPN), especially in JAK2V617F-positive cases was reported [3,4]. But there was only one study [3] and re-published [5] in 36 patients reported by Chinese researcher group about the relation between 'C' allele rs3184504 and Ph-positive chronic myeloid leukemia (CML).

To explore an association of this LNK polymorphism with chronic myeloproliferative disorders, we analyzed whole-blood DNA samples of 177 patients with suspicion MPNs including 55 with polycythemia vera (PV), 37 with essential thrombocythemia (ET), and 43 with myelofibrosis (MF) which were subsequently verified. Blood samples of 83 patients with CML were also tested. The diagnosis was based on WHO classification. Polymorphism of LNK (rs3184504) and the JAK2V617F mutation were determined by allele-specific PCR-RT using the 'Gene Formula LTD' commercial kit 'LNK R262W.' Calculation of Hardy-Weinberg equilibrium and genotype frequencies was assumed using the SNPassoc R package. Statistical significance was set at the level of p < .05.

The results have been shown in Table 1. Our control group included 182 samples of blood donors from Krasnoyarsk Blood Center. 'T' and 'C' alleles distribution of rs3184504 did not differ between our healthy subjects and another control groups without hematological disorders of 177 Russian [6] or 2851 Spanish [7] subjects. 'T' allele occurred more frequently in patients with myeloproliferative disorders as compared with control, although statistically significant differences were observed in PV and JAK2V617F-positive patients only. We did not find association between the genotype of LNK polymorphism and the percentage of JAK2V617F allele burden. This result is consistent with those of Lesteven et al. [4].

Frequency of LNK/SH2B3 c.784T > C in MPNs, CML, and controls.

1 PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; WT: wild-type; OR: odds ratio; CI: confidence interval. Bold values represents statistically significant difference with p < .05.

It is obvious that proinflammatory cytokines do not have adequate counteraction for the activation of the Janus kinase if there is allele 'T' of this LNK polymorphism. And as it is known, the 'cytokine storm' and inflammation in the bone marrow causes of MPN progression [8,9].

But our data do not fully agree with the data of the Chen Y study group [3,5], and we cannot confirm the predominance of the 'C' allele in patients with CML. In addition, in the study of Chen et al. was not found heterozygotes in groups of MPN and CML patients that differ from the findings presented in our research. A possible explanation for these results may be ethnic differences between European and Asian populations. This assumption is confirmed in the database of 1000 genomes [10], where regional differences in the distribution of genetic polymorphism LNK (rs3184504) were found. 'C' allele predominates in Asian and African populations (>90%), which was significantly higher than in the European populations (<75%).

Finally, we confirmed of the minor 'T' allele of LNK polymorphism determines fertile ground for the development of JAK2V617F positive MPN. However, we did not find any association of the 'C' allele of this LNK gene with CML in our patients and do not see any clear reasons for such an association, except for the ethnic features of the LNK (rs3184504) polymorphism.

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