JANUS KINASE V617F MUTATION DETECTION IN PATIENTS WITH MYELOFIBROSIS
Nikolova D1,2,*, Yordanov A2, Damyanova V1,2, Radinov A2, Toncheva D1
*Corresponding Author: Dragomira Nikolova, Ph.D., Department of Medical Genetics, Medical Faculty, Medical University Sofia, 2 Zdrave Street, 1431 Sofia, Bulgaria. Tel: +359888-103-456, E-mail: dmb@abv.bg
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DISCUSSION

Extramedullary hematopoiesis, overstimulated fibroblasts in abnormal microenvironment, fibrous tissue deposits in the bone marrow, dysregulation of the normal production of blood cells, low count of platelets and subsequently the onset of anemia are characteristic hallmarks of MF. Generally, it is a rare hematological event, predominantly diagnosed in elderly individuals aged over 50 years [14-16]. The MF/OMF patients were also rare in our dataset (20/232 patients confirmed the diagnosis, 8.6%) and the mean age of the patients was 62 years. The gender does not affect the occurrence of the disease; there is an equal distribution men:women (10 vs. 10). The total survival time of patients with PMF can vary substantially, as well as the clinical course of the disease and its progression. It can be diagnosed as primary or developed as a part of other hematological malignancies as PV or ET. However, the mechanisms of development of MF are not completely understood. The JAK2, together with CALR and MPL mutations, is a common triggering factor in Philadelphia chromosome-negative MPNs [17]. The so-called “driver” mutations activate the JAKSTAT signaling pathway. According to previous reports, about 85.0% of PMF patients have affected one of the three genes: JAK2 (60.0-65.0%), MPL (5.0%) or CALR (20.0-25.0%) [14]. In our study, 20 patients with MF were analyzed for JAK2 mutation by quantitative PCR; and 12 of them carried the mutant allele (60.0%), which is in accordance with the data reported by other researchers [4]. The remaining patients (12 individuals) who were accepted with an initial diagnosis of MF, five were confirmed to carry ET, six with PV and one remained an unclassified MPN. This showed that trepanobiopsy is absolutely essential for the final precision of the diagnosis. The discovery of the genetic transformation of the JAK2 gene in the majority of our cases with MF makes possible their treatment with Jakafi (Ruloxitinib), which is an approved targeted drug for MF. It is indicated both for primary and secondary MF, either high- or intermediaterisk groups. It helps to reduce side effects such as splenomegaly, abdominal and bone pain. At the same time, it controls the blood levels of the inflammatory cytokines. The JAK2 V617F mutation leads to constitutive activation of JAK/STAT signaling [9]. As the JAK2 mutation is present in only about 60.0% of patients with MF, it could not be considered to be the only reason for this pathology. The triggering event of MF is not yet clarified and other mutations besides JAK2 have recently been studied in relation to MF. They include mutations in genes such as IDH1, IDH2, ASXL1, SRSF2 and EZH2 [2]. In 2019, Wilms tumor 1 (WT1) expression was investigated in 152 patients with MPNs [18]. The progression of ET and PV to MF was accompanied by increased levels of WT1 gene expression. Mutations in a tumor-suppressor gene, TP53, have also been detected in MPN, especially on older patients [19]. Some cytogenetic transformations (e.g., additional chromosome 8, inversion of chromosome 3 and rearrangements of chromosome 11) have been considered unfavorable markers for MF [20]. Even though the number of MF patients in our study are quite few (20 individuals), we could underline the slight prevalence of males in the mutant allele carriers (seven men vs. five women), while in the group of non carriers, females prevailed slightly (three men vs. five women). As for the age of the patients, the registered difference between carriers and non carriers of the JAK2 V617F mutation was 1 year (mean age of carriers:non carriers = 61.4:62.4 years). Whether the male gender and younger age are factors that contribute to JAK2 mutational status is disputable and has to be further investigated in a larger cohort of MF patients. We have not had a case in which the JAK2 mutation occurs simultaneously with other mutations, as it generally occurs as a single event. However, it could be associated with a different severity of symptoms from asymptomatic ET to MF [19]. We could speculate that other factors rather than genetic could modify the severity of the disease (for example age, gender, comorbidity, microenvironment in the bone marrow, etc.) [19]. The frequency of MF in our cohort of patients (232 individuals) was estimated to be 8.6% (20 individuals). The distribution was equal between genders and the mean age (63.95 years) approaches the mean age given by other researchers (65 years). The majority of MF patients (60.0% or 12 individuals) were JAK2 V617F mutation-positive and thereby treatable by Jakafi (Ruxolitinib). For the other 40.0% of cases (eight individuals), treatment options were limited. They included erythropoiesis-stimulating agents, hydroxyurea and immunomodulatory drugs, which have unconvincing effect in improving patients’ survival. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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