About MPN

Philadelphia-negative myeloproliferative neoplasms (MPNs) are rare clonal diseases characterized by chronic elevation of blood cell counts (red blood cells, platelets, granulocytes), splenomegaly, and fibrosis of the bone marrow.There are three MPNs: polycythemia vera (PV), characterized by overproduction of red blood cells; essential thrombocythemia (ET), characterized by overproduction of platelets; and primary myelofibrosis (PMF), characterized by splenomegaly and fibrosis of the bone marrow.

In 2005, the discovery in Europe of the V617F mutation in the JAK2 gene in the majority of MPNs has renewed interest in these diseases.1. Since 2005,mutations in two other genes, MPL(2006) and CALR (2013), have been discovered in MPNs with no JAK2V617F mutation.2,3. Consequently, new diagnostic tools have being designed to detect and quantify the JAK2V617F mutation, as well as the MPLW515L/K and CALR mutations characteristic of MPNs. In addition, several other genes have been described as mutated in MPNs, as well as in other hematological malignancies; some of the additional mutations may serve as pronostic markers. Similar progress has been made in the rare congenital/hereditary diseases related to MPNs (MPNr), such as congenital erythrocytosis (CE) and hereditary thrombocytosis (HT). Several genes have been described as abnormal in these diseases but the diagnosis of patients remain difficult and too often, not done.

In 2007, a group of European biologists decided toshare their expertiseinthe new molecular assays designed to detect the mutations identified in MPNsand in MPN-related diseases. This informal network led tothe first international comparative study of JAK2V617F assays, in an effort to harmonize the detection and improve the quantification of the main MPN mutation.4. The new European network was made official as MPN&MPNr-EuroNet in November 2009 thanks to the creation of COST Action BM0902, funded by the Co-Operation in Science and Technology (COST) programme, until November 2013. MPN&MPNr-EuroNet, now strong of 155 members representing 32 countries, fosters cooperation among European MPN experts to improve understanding of MPNs and related hereditary diseases and tofacilitate and harmonize the diagnosis of these diseases in Europe. Each spring, MPN&MPNr-EuroNet organizes an international meeting, open to all. Since 2014, the network has been supported by the MPN&MPNr-EuroNetFund, within the Project Foundation of the Université of Nantes, France.

References

1. James Cet al. A unique clonal JAK2mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144-8.
2. Pikman Y et al. MPLW515L is a novel somatic activating mutationin myelofibrosis with myeloid metaplasia.PLoS Med 2006; 3 :e270.
3. Klampfl Tet al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369: 2379-90.
4. Jovanovic JV et al. Establishing Optimal Quantitative-Polymerase Chain Reaction Assays for RoutineDiagnosis and Tracking Minimal Residual Disease in JAK2V617F Associated Myeloid Neoplasms: A Joint European LeukemiaNet/ MPN&MPNr-EuroNet (COST Action BM0902) Study. Leukemia 2013;27(10):2032-2039.

Since 2009 MPN&MPNr-EuroNet has optimized JAK2V617F assays and determined reference JAK2V617F standards. During the 2009-2013 period, joint collaborative studies between MPN&MPNr-EuroNet and European Leukemia Net led to the determination of the optimal JAK2V617F assays recommended for diagnostic use in Europe (Jovanovic et al.,2013). These studies indicated a strong need for reference materials to enable standardization of JAK2V617F testing and quantification (Lippert et al.,2009; Asp et al.,2017). More recently, MPN&MPNr-EuroNet collaborated with the National Institute of Biological Standards and Controls (NIBSC, UK) to producea panel of genomic JAK2V617F-mutated reference DNAs, which was approved in October 2016 by the World Health Organization (WHO) as the 1st WHO International Genomic Reference Panel for JAK2V617F, for both mutation detection and quantification.Regarding CE and HT, MPN&MPNr-EuroNet has centralized and organized the detection of the main CE-and HT-associated mutations, notably by using Next Generation sequencing (NGS). MPN&MPNr-EuroNet has also helped diffuse information about these very rare diseases, including via publications and reviews (Hussein et al.,2014; Bento et al.,2014).Thanks to the COST program, in 2014 abook dedicated to CE and HThas been published. Altogether, MPN&MPNr-EuroNet has published 22 articles or reviews (listed below). Finally, since 2009, MPN&MPNr-EuroNet has helped communication and scientific exchanges between researchers, biologists and clinicians via the organization of 14 international meetings dedicated to MPNs, CE and HT.

1. Lippert E et al. Concordance of assays designed for the quantitation of JAK2V617F(1849G>T): a multi-centre study. Haematologica 2009; 94: 38-45.
2. www.nibsc.org/science_and_research/advanced_therapies/genomic_reference_materials/jak2_v617f_
3. Cario H et al. Erythrocytosis in children and adolescents -classification, characterization, and consensus recommandations for the diagnostic approach. Pediatr Blood Cancer 2013; 60:1734-38.
4. Hussein Ket al. Clinical utility gene card for: Hereditary thrombocytosis. Eur J Human Genet 2014; 22(2). doi: 10.1038/ejhg.2013.117.Jun 5.
5. Bento C et al.; on behalf of ECE-Consortium. Genetic basis of Congenital Erythrocytosis: mutation update and online databases. Human Mutation 2014; 35:15-26. doi: 10.1002/humu.22448.
6. Gardie Bet al.The role of PHD2 mutations in the pathogenesis of erythrocytosis. Hypoxia 2014; 2:71-90. eCollection 2014. Review.
7. Gross M et al. Polycythaemia-inducingmutations in the erythropoietinreceptor (EPOR): mechanismand functionas elucidatedby EGF receptor-EPOR chimeras. Br J Haematol 2014; 165(4):519-28.
8. BentoCet al.,on behalf of COST Action BM0902 (MPN&MPNr-EuroNet). Congenital Erythrocytosis &Hereditary Thrombocytosis (Book), 2014.
9. Lippert E et al. Clinical and biological characterization of patients with low (0.1-2%) JAK2V617F allele burden at diagnosis. Haematologica 2014; 99 (7): e098-101.
10. Barosi G et al. Clinical endpoints for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from ELN and IWG-MRT. Leukemia 2015; 29(1):20-6. doi:10.1038/leu.2014.250. Review.
11. Langabeer SE et al., on behalf of the MPN&MPNr-EuroNet.Molecular diagnostics of myeloproliferative neoplasms (MPN). Eur J Hematol 2015;95(4):270-9. doi: 10.1111/ejh.12578.
12. Hermouet S, Hasselbalch HC, Cokic V. Mediators of inflammation in myeloproliferative neoplasms: State of the Art. Mediators Inflamm 2015; 964613. doi: 10.1155/2015/964613. Editorial.
13. Hermouet S et al. Pathogenesis of myeloproliferative neoplasms: Role and mechanisms of chronic inflammation. Mediators Inflamm 2015; 145293. doi: 10.1155/2015/145293. Review.
14. McMullin MFet al. Outcomes of pregnancy in patients with congenital erythrocytosis. Br J Haematol 2015;170(4):586-588.
15. McMullin MF, Cario H. LNK mutations and myeloproliferative disorders. Am J Hematol 2016; 91(2):248-251. Review.
16. Panovska-Stavridis Iet al. Essential Thrombocythemia associated with germline JAK2 G571S variant and somatic CALR type 1 mutation. Clin Lymphoma Myeloma Leuk 2016; 16(5):e55-7.
17. Bento Cet al. Primary Familial and Congenital Polycythemia. Gene Reviews. 2016. University of Washington, Seattle.
18. Biagetti G et al. HFE mutations in idiopathic erythrocytosis. Haematologica 2016; 101:1306-1318.
19. Camps Cet al. Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. Br J Haematology 2017; Feb 7 PMID: 28169423
20. Cleyrat Cet al.Gene Editing rescue of a novel MPLmutant associated with congenital amegakaryocytic thrombocytopenia.Blood Advances 2017; 1:1815-1826.
21. Catherwood MAet al.Absence of CALR mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels. Acta Haematologia 2018; 139(4):217-219. doi: 10.1159/000489006.
22. Asp J et al. International quality assurance of JAK2V617F quantification. Annals Hematol 2019; 98(5):1111-1118. doi: 10.1007/s00277-018-3570-8