Impact of JAK2V617F Mutational Status on Clinical and Laboratory Phenotype at Diagnosis and during Follow-up in Patients with Essential Thrombocythemia
Authors: Elli Elena , Belotti Angelo , Parma Matteo , Colnaghi Federica , Colombo Arianna , Lanzi Eraldo , Pioltelli Pietro , Pogliani Enrico Maria 
Published: April 2020

Abstract
BACKGROUND: Essential thrombocythemia (ET) is thought to derive from the transformation of a multipotent hematopoietic stem cell, but its molecular pathogenesis remains obscure. An acquired mutation in exon 14 of the Janus tyrosine kinase 2 gene (JAK2) leading to a valine --&gt; phenylalanine change at position 617 (JAK2V617F) in the JH2 pseudokinase domain, has been described in Ph negative chronic myeloproliferative disorders (MPD). It can be found in approximately 95% of polycythemia vera (PV) and in approximately 50–60% of essential thrombocythemia (ET) or primary myelofibrosis. The impact of this mutation on clinical phenotype is still debated. We investigated the frequency of JAK2 mutation and its possible impact and correlation with clinical and laboratory features at diagnosis and during follow-up in ET patients (pts), screened for JAK2 mutational status, referred to our division between 1987 and 2008.
METHODS and PATIENTS: JAK2V617F mutation analysis was performed on genomic DNA from bone marrow cells or peripheral blood granulocytes in 115 ET (49 males, 66 females) pts, using allele-specific PCR. Clinical and laboratory features were evaluated at diagnosis and during follow-up, in order to compare ET pts harbouring JAK2 mutation versus (vs) pts harbouring wildtype (WT) gene. For statistical analysis, data were processed using the Graph Pad PRISM 5 DEMO Software. Correlations between clinical variables and JAK2 V617F mutational status were tested for significance (p value &lt; 0,05) by using non-parametric methods, in particular the chi-square test or Fisher’s exact test (two by two table) for categorical nominal variables and the Mann-Whitney rank test for ordinal variables. The log-rank (Mantel-Cox) test applied to Kaplan-Meyer method was employed to estimate thrombotic risk and thrombotic event-free-survival (TEFS)
RESULTS: 66 ET pts (57,4%) were JAK2V617 positive. JAK2 mutated pts were older (median age 59 vs 48 years, p = 0,0016) and presented at diagnosis significantly higher hemoglobin levels (Hb 14,3 g/dl vs 13,3 g/dl, p= 0,0027), higher hematocrit (Ht 43% vs 39,8%, p &lt; 0,0001) and lower PLT count (PLT 725 vs 841 ×109/L, p = 0,005) respect to WT group. These PV-like features have also maintained during the course of disease, with statistical significance. No difference was observed in term of gender, white blood count, LDH, progression or entity of splenomegaly, and need of cytoreductive therapy between JAK2 mutated and WT ET pts. A highly significant increase of thrombotic complications was registered for JAK2 positive pts. Considering JAK2 WT ET as reference group, the relative risk (RR) of primary thrombotic event was 2,143 (95% CI: 1.053–4.360, p = 0,035) for JAK2 mutated pts (TEFS at 15 years of 60% in JAK2 mutated group vs 75% in WT group, respectively). Arterial events were more frequent than venous events without statistical difference between two ET groups. A trend of higher risk of recurrent thrombosis (p = 0,056) was also showed for JAK2 mutated respect to WT ET pts. There was no difference about the risk of haemorragic complications, time and incidence of evolution in myelofibrosis between JAK2 mutated or WT ET pts.
CONCLUSION: In our population, 57,4% ET pts harbor JAK2V617F mutation. This mutation divides ET pts into two distinct subtypes. JAK2 mutated ET pts present older age and laboratory features at diagnosis and during follow-up, compatible with PV-like phenotype. An increased risk of thrombosis, at diagnosis and during the course of disease, has been showed in mutated ET group, in term of recurrent thrombosis too. These observations seem to confirm a phenotype more aggressive since the diagnosis in JAK2 mutated ET group. A possible biological continuum between JAK2 mutated ET and PV, or more in general between JAK2 positive ET and MPD may be supposed.