BIOMOLECULAR AND HEALTH SCIENCE JOURNAL 2018 NOVEMBER, 01 (02) 135 REVIEW ARTICLE The Role of JAK2 in Myeloproliferative Diseases Diagnosis Yudith Annisa Ayu Rezkitha1* 1Department of Internal Medicine, Faculty of Medicine Universitas Airlangga - Dr. Soetomo General Hospital Surabaya, Indonesia A R T I C L E I N F O A B S T R A C T Article history: Janus Kinase 2 (JAK2) plays an important role in mediating transduction signal of Received 25 September 2018 hematopoiesis, including in the pathogenesis of Myeloproliferative diseases (MPD). Various studies have been carried out to identify the position of aleles in tyrosine encoding Received in revised form 15 mutations. Although the effect of JAK2 mutations is still not fully understood, the October 2018 discovery of these mutations might be able to differentiate the types of polycythaemia vera, Accepted 1 November 2018 essential thrombocytemia, and primary myelofibrosis with malignant abnormalities. WHO Available online 30 November has revised the MPD diagnosis criteria following this finding. This review will discuss the 2018 role of JAK2. Keywords: Janus Kinase 2, . Myeloproliferative disease, Mutation. *) Corresponding author: [email protected] Introduction of the JAK2V617F mutation provides a way to Myeloproliferative diseases (MPD) are clonal differentiate polycythaemia vera, ET and PMF with abnormalities of hematopoiesis progenitors. This group benign and malignant abnormalities that are clinically 2 consists of two main groups, namely the Philadelphia similar, although they cannot distinguish between them. positive chromosome group Chronic Myeloid Leukemia Although the latest information about the effect of (CML), the negative Philadelphia chromosome group JAK2 mutations on the pathogenesis and prognosis of namely Polycythemia Vera (PV), Essential MPD is still not entirely clear, various evidences about Thrombocytemia (ET) and Primary Myelofibrosis JAK2 has made the World Health Organization (WHO) 3 (PMF), as well as the rare MPD group such as Chronic revise the criteria for MPD diagnosis. Eosinophilic Leukemia (CEL), Chronic Myelomonocytic Leukemia (CMML), and Systemic Mastocytosis (SM).1 JAK2 Janus Kinase 2 (JAK2) is a part of tyrosine kinase The human body is able to express more than 500 protein that is important for cytokine receptors and plays a role kinases. There are 2 types of tyrosine type protein in mediating signal transduction from various immune kinases namely receptor and cytoplasm types. Protein responses, growth, cell differentiation, and tyrosine kinase receptor types include Platelet-Derived hematopoiesis. It is now known that mutations in JAK2 Growth Factor Receptors (PDGFR), stem cell factor will cause constitutive activation of the JAK pathway. receptor (KIT), Fibroblast Growth Factor Receptor Various studies have been conducted to identify the (FGFR), Vascular Endothelial Growth Factor Receptor position of the activated alele, causing a constitutive (VEGFR), and fms-related tyrosine kinase 3 ( Flt3), abnormality in tyrosine kinase encoding. The discovery whereas cytoplasmic type tyrosine kinase proteins are Biomolecular and Health Science Journal Available at https://e-journal.unair.ac.id/BHSJ ; DOI: 10.20473/bhsj.v1i2.9831 This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. BIOMOLECULAR AND HEALTH SCIENCE JOURNAL 2018 NOVEMBER, 01 (02) 136 the janus kinase group (JAK), the Src kinase group inhibition of STAT binding DNA by Protein Inhibitors (SFKs), and the ABL kinase.4, 5 of Activated STAT (PIAS).10, 11 JAK plays an important role in hematopoietic cells cytokine signaling. JAK is involved in signal JAK2 Mutation transduction in type 1 cytokine receptors, namely for In the context of hematopoiesis, encoding JAK-STAT is Interlekuin (IL) -2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-13, essential for definitive hematopoesis and cytokine Granulocyte Macrophage-Colony Stimulating Factor response in myeloid progenitors, therefore it is not (GM-CSF), Growth Hormone (GH), Prolactin (PRL), surprising if mutations from molecules related to JAK- Erythropoietin (EPO), and Thrombopoietin (TPO), as STAT encoding or its regulators will be related to well as type 2 receptors, namely Interferon (IFN) -α, hematological malignancies.4, 12 6 IFN-β, and IFN- γ. JAK2V617F is an exon 14 G to T somatic mutation There are currently 4 JAK groups, namely JAK1, in JAK2 which resulted in substitution of valine to 7 JAK2, JAK3 and Tyk2. JAK is divided into 7 areas phenylalanine at codon 617. JAK2V617F association called domains 1-7 JAK homology (JH) (figure 1). The with MPD, including PV, ET, and PMF, was first JH1 domain is catalytic phosphotyrosine kinase, the JH2 reported in 2005. JAK2V617F is not found in lymphoid domain functions as a pseudokinase domain and is disorders, solid tumors, or secondary believed to be able regulate both basal JAK activity and myeloproliferation.4 This mutation cause signal to activate catalytic induced receptor function. transmission to become more sensitive and efficient than Interestingly, because of the absence of ligand bond, EPO receptor, TPO receptor, and G-CSF receptor to interaction of JH1 and JH2 domains will manifest an haematopoietic cells and cause loss of autoinhibition of autoinhibition device, means if there is a change in this JAK2 activity.13, 14 area there will be autoinhibition dysregulation. The JH3- Detection of JAK2V617F mutation can be done with JH4 domain is a homologous domain with the Src- alel-specific PCR that use neutrophil. A positive test homology-2 (SH2) domain, but not linked to result strongly indicated MPD because it is usually phosphotyrosine residues. The JH5-JH7 is the FERM negative in all normal individuals and hematological domain (Four-point-one, Ezrin, Radxin, Moesin), which abnormalities such as secondary erythrocytosis, reactive 6, 8, 9 mediates JAK and other proteins. thrombocytosis, leukemoid reactions, and secondary myelofibrosis. This test is also negative for normal B lymphocytes, normal T lymphocytes, lymphoma, sarcoma, and solid tumors. In addition, this test is also usually negative for chronic myeloid leukemia, acute myeloid leukemia (except those who develop from MPD), and myelodysplastic syndrome. In addition, the test can also be useful as a sensitive marker of MPD Figure 1. Domain of Janus homolog JAK family of detection as a basic etiology of splanchnic venous kinases. thrombosis affecting the spleen vein, portal vein, and hepatic vein.13 Under normal conditions, activation of JAK-STAT (signal transducers and activators) is initiated by ligand Impact on Diagnosis bonds and receptors which then induce receptor PV patients often show symptoms like headache, dimerization, which results in auto-transfusion of JAK2- pruritus, vaso-occlusive symptoms such as tinnitus, related receptors. The part of the phosphorylated receptor paresthesia, and erythromelalgia. Splenomegaly is seen will then act as a place for the recruitment and in some patients with a size that is directly proportional phosphorylation of signal-sending molecules, that to the stage of the disease. Typical characteristics of PV triggers the encoding process through STAT resulting in are high hematocrit, erythrocytosis, and increased dimerization and translocation of the STAT molecule hemoglobin levels. Bone marrow biopsy shows into the nucleus where the interaction with specific hypersellularity with increased proliferation of three regulatory elements will induce target gene lines (panmielosis), especially erythroid, granulocytic 10 transcription. proliferation, and megakariocytic.15 The number and duration of JAK2 encoding are The actual erythrocyte volume status is not enough if strictly regulated by several mechanisms to prevent only described by hemoglobin levels and hematocrit unnecessary encoding which can lead to uncontrolled alone. Increased hemoglobin and hematocrit levels can proliferation and transformation towards malignancy. show a true polycythemia (increased erythrocyte The mechanisms include JAK2 direct dephosphorylation volume) or apparent polycythemia (not associated with by certain protein tyrosine phosphatase (such as SHP-1), increased erythrocyte volume). True polycythemia proteolytic degradation of JAK2 by binding in with includes PV and non-clonal erythrocytosis, namely Suppressors of Cytokine Signaling (SOCS) and secondary polycythemia (mediated by EPO). While apparent polycythemia is a result of plasma volume BIOMOLECULAR AND HEALTH SCIENCE JOURNAL 2018 NOVEMBER, 01 (02) 137 decrease (relative polycythemia). Inapparent PV used to mutations that were not EPO dependent.3, 11 describe PV patients who have an increase in erythrocyte ET is clinically characterized by thrombosis, volume but are obscured by normal hematocrit values headache, dizziness, syncope, acrosianosis, and changes due to an increase in plasma volume. Therefore, in in vision. Mild splenomegaly occurs in 40% of patients, suspected PV patients, secondary polycythemia and but 25-35% of cases are asymptomatic and are diagnosed apparent polycythemia must be excluded.4 accidentally. Based on laboratory examination, ET is In PV patients, erythroid progenitors can grow characterized by thrombocytosis and megacryocyte without the addition of exogenous erythropoetin, which hyperplasia in bone marrow examination, without is the initial etiological factors in cytokine regulation. accompanied by erythrocytosis and leukoeritroblastosis. JAK2 mutation was finally approved to be the main Megakariocyte