Myeloproliferative neoplasms (MPN) are characterized by clonal expansion of one or more lineages of differentiated myeloid, erythroid, and megakaryocytic cells due to abnormal hematopoietic stem cells. BCR/ABL-negative MPN include polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The molecular pathogenesis of MPN long remained unknown, but following the discovery of the JAK2 gene mutation in 2005, many additional gene mutations, including other driver mutations, were identified, and the molecular pathogenesis of MPN was rapidly elucidated. The discovery of JAK2 gene mutations has led to the development of JAK2 inhibitors, which are now being introduced into clinical practice. Information on gene mutations in MPN is expected to be used not only in MPN diagnosis, but in disease risk assessment, prognosis prediction, therapeutic decision-making and post-treatment monitoring, and the identification of target candidates for new molecular target drugs.
A number of discoveries followed that of the JAK2 mutation in 2005 , including the JAK2 Exon12  the MPLW515 [3, 4] mutation and more recently, at the end of 2013 the CALR mutation, [5, 6]. Analyses to date indicate that nearly 90% of BCR/ABL-negative MPNs involve at least one of the above mutations, and these mutations were included in the diagnostic criteria in the revised WHO classification 2017 . Analysis of mouse models reveals that any one of these gene mutations alone can cause the pathology of MPN; for this reason, such sequence variants are called driver mutations. In the Progress in Hematology (PIH) section in this issue, Shide and Shimoda summarize the pathological analysis of MPN in a mouse model with a driver mutation, including findings from their own analytic approach. While JAK2 and MPL are gain-of-function mutations, CALR forms a new C-terminus by frameshift, and this mutation site binds to the extracellular N-domain site of MPL and activates MPL signaling in a thrombopoietin-independent manner . Arai and Komatsu are intensively studying the pathogenesis of MPN caused by the CALR mutation, and they outline the role of CALR mutation in MPN, including their own results. Jia and Kralovics provide a general overview of the pathogenic role of genetic mutations in MPNs. In addition to driver mutations, various other gene mutations contribute to the pathogenesis of MPN development. Although the frequency of detection of each mutation is low, mutations affecting TET2, DNMT3, IDH1/2 (a methylation-related regulator), EZH2 (a histone modification-related factor), and ASXL1, as well as mutations of RNA splicing molecules, have also been reported. These mutations are involved in the development and progression of MPN . In the future, evaluation of these driver and non-diver gene mutations in MPN will be essential for diagnosis and assessment of prognosis.
Primary myelofibrosis, unlike other MPNs, has a significantly worse prognosis . Although hematopoietic stem cell transplantation is the only curative treatment, its indication is limited due to the age of onset. Disease risk should thus be assessed individually, and used to guide the development of the treatment plan. International Prognostic Scoring System for PMF (IPSS), Dynamic IPSS (DIPSS), and DIPSS-plus are widely used scoring systems that predict prognosis using clinical and hematological findings as risk factors . Although these are systems that can easily evaluate risk at the bedside, information on genetic mutations is not included among the risk factors. However, recently, a scoring system using various gene mutation information as risk factors has been proposed [12, 13], and it was found that some patients who were categorized to the low-risk group under the conventional scoring system were assigned to the high-risk using a scoring system that includes gene mutation information. Bose and Verstovsek provide an overview of gene mutation information in MPN and summarize prognostic models for PMF based on genetic information.
A JAK2 inhibitor has been developed to target activation of the JAK2 signal, which is central to the pathology of MPN, and the JAK2 inhibitor ruxolitinib was introduced to clinical practice in Japan in 2014. The application of gene mutation information to therapy in MPL is also reviewed by Jia et al. and Bose et al.
This PIH focuses on the importance of gene mutation information in MPN in diagnosing MPN and deciding treatment strategies. However, in Japan, the analysis of these gene mutations is not covered by the national health insurance system, and it is difficult to conduct routine tests outside the context of research. Establishment of a system for analysis of gene mutations in Japan is much needed.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61.
Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–68.
Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270.
Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006;108(10):3472–6.
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90.
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.
Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, et al. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. Blood. 2016;127(10):1307–16.
Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667–79.
Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507–13 quiz 615.
Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392–7.
Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36(4):310–8.
Tefferi A, Guglielmelli P, Lasho TL, Gangat N, Ketterling RP, Pardanani A, et al. MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for primary myelofibrosis. J Clin Oncol. 2018;36(17):1769–70.
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Takenaka, K. Progress in elucidation of molecular pathophysiology and its application in therapeutic decision-making for myeloproliferative neoplasms. Int J Hematol 111, 180–181 (2020). https://doi.org/10.1007/s12185-019-02812-w