AccScience Publishing / GTM / Online First / DOI: 10.36922/gtm.2559
Submit to GTM
Cite this article
54
Download
667
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

The PAI-1 4G/5G polymorphism, JAK2V617F mutation, and their associations with blood cells in Ph-negative myeloproliferative neoplasms

Yevhen Dzis1* ,  Oleksandra Tomashevska1 ,  Myroslav Voroniak2 ,  Nataliia Shelep2 ,  Sofiia Khudzii2 ,  Ivan Dzis3
Show Less
1 Department of Internal Medicine No. 2, Faculty of Dentistry, Danylo Halytsky Lviv National Medical University, Lviv, Lviv Oblast, Ukraine
2 Laboratory of Molecular Genetics, Institute of Blood Pathology and Transfusion Medicine of the National Academy of Medical Sciences of Ukraine, Lviv, Lviv Oblast, Ukraine
3 Department of Therapy, Medical Diagnostics, Hematology and Transfusiology, Faculty of Postgraduate Education, Danylo Halytsky Lviv National Medical University, Lviv, Lviv Oblast, Ukraine
Global Translational Medicine 2024, 3(2), 2559 https://doi.org/10.36922/gtm.2559
Submitted: 28 December 2023 | Accepted: 18 April 2024 | Published: 19 June 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Factors influencing the urokinase-type plasminogen activator system play important roles in pathogenetic processes in Ph-negative myeloproliferative neoplasms (MPNs). In addition, the JAK2V617F mutation is a key determinant of outcomes in these diseases. This study evaluated complete blood count (CBC) parameters, the plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphism, and the JAK2V617F mutation in patients with Ph-negative MPNs, aiming to identify possible associations between them. We analyzed results from 56 patients newly diagnosed with Ph-negative MPNs— essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF)—before treatment initiation. The CBC of 475 people from a diagnostic center database served as a population sample for comparison. In patients with Ph-negative MPNs, PAI-1 genotypes 4G/4G, 4G/5G, and 5G/5G were detected in 11 (19.6%), 29 (51.8%), and 16 (28.6%) cases, respectively. No significant differences in genotype distribution were found among ET, PV, and PMF patients. PMF patients with the 4G/5G genotype had a higher white blood cell (WBC) count compared to those with the 5G/5G genotype (P = 0.027). The JAK2V617F mutation was found in 44 (78.6%) patients. ET patients with this mutation (n = 13) exhibited significantly higher counts of platelets (PLTs), red blood cells (RBCs), and WBCs compared to those without it. The PLT/RBC ratio was significantly higher in all disease categories compared to the population sample, with the highest ratios in ET patients. The PLT/WBC ratio in ET and PV patients was also higher than in the population sample (P < 0.05). This relative thrombocytosis is likely clonal in origin, associated with genes responsible for PLT quantitative parameters, JAK-STAT signaling pathway proteins, and factors in the uPA-uPAR-PAI-1/PAI-2 system. These genes share common loci in chromosomes (1p34.1-p34.3, 7q21.1-q21.3, 9p24.1, 19p13.11-p13.2, and 19q13.31-q13.32). Due to their close spatial proximity, these genes can form genetic complexes and mutually influence their expression levels, thereby contributing to the unique pathogenesis of these diseases.

Keywords
Ph-negative myeloproliferative neoplasms
PAI-1 4G/5G polymorphism
JAK2V617F mutation
Complete blood count
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Coltro G, Loscocco GG, Vannucchi AM. Classical Philadelphia-negative myeloproliferative neoplasms (MPNs): A continuum of different disease entities. Int Rev Cell Mol Biol. 2021;365:1-69. doi: 10.1016/bs.ircmb.2021.09.001

 

  1. Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: Integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi: 10.1182/blood.2022015850

 

  1. Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 2017;129(6):680-692. doi: 10.1182/blood-2016-10-695957

 

  1. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667-679. doi: 10.1182/blood-2016-10-695940

 

  1. Chachoua I, Pecquet C, El-Khoury M, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127(10):1325-1335. doi: 10.1182/blood-2015-11-681932

 

  1. Falanga A, Marchetti M. Thrombosis in myeloproliferative neoplasms. Semin Thromb Hemost. 2014;40(3):348-358. doi: 10.1055/s-0034-1370794

 

  1. Chia YC, Siti Asmaa MJ, Ramli M, et al. Molecular genetics of thrombotic myeloproliferative neoplasms: Implications in precision oncology. Diagnostics (Basel). 2023;13(1):163. doi: 10.3390/diagnostics13010163

 

  1. Marin Oyarzún CP, Heller PG. Platelets as mediators of thromboinflammation in chronic myeloproliferative neoplasms. Front Immunol. 2019;10:1373. doi: 10.3389/fimmu.2019.01373

 

  1. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14(8):e1002533. doi: 10.1371/journal.pbio.1002533

 

  1. Bianconi E, Piovesan A, Facchin F, et al. An estimation of the number of cells in the human body. Ann Hum Biol. 2013;40(6):463-471. doi: 10.3109/03014460.2013.807878

 

  1. Li Santi A, Gorrasi A, Alfieri M, Montuori N, Ragno P. A novel oncogenic role for urokinase receptor in leukemia cells: Molecular sponge for oncosuppressor microRNAs. Oncotarget. 2018;9(45):27823-27834. doi: 10.18632/oncotarget.25597

 

  1. Santibanez JF. Urokinase type plasminogen activator and the molecular mechanisms of its regulation in cancer. Protein Pept Lett. 2017;24(10):936-946. doi: 10.2174/0929866524666170818161132

 

  1. Irmak-Yazicioglu MB, Ergun K. Role of plasminogen activator inhibitor-1 (PAI-1) in cancer stem cells. WCRJ. 2022;9:e2252. doi: 10.32113/wcrj_20223_2252

 

  1. Kunz C, Pebler S, Otte J, von der Ahe D. Differential regulation of plasminogen activator and inhibitor gene transcription by the tumor suppressor p53. Nucleic Acids Res. 1995;23(18):3710-3717. doi: 10.1093/nar/23.18.3710

 

  1. Jensen MK, Riisbro R, Holten-Andersen MN, et al. Collagen metabolism and enzymes of the urokinase plasminogen activator system in chronic myeloproliferative disorders: Correlation between plasma-soluble urokinase plasminogen activator receptor and serum markers for collagen metabolism. Eur J Haematol. 2003;71(4):276-282. doi: 10.1034/j.1600-0609.2003.00134.x

 

  1. Westerhausen DR Jr., Hopkins WE, Billadello JJ. Multiple transforming growth factor-beta-inducible elements regulate expression of the plasminogen activator inhibitor type-1 gene in Hep G2 cells. J Biol Chem. 1991;266(2):1092-1100.

 

  1. Rabieian R, Boshtam M, Zareei M, Kouhpayeh S, Masoudifar A, Mirzaei H. Plasminogen activator inhibitor type-1 as a regulator of fibrosis. J Cell Biochem. 2018;119(1):17-27. doi: 10.1002/jcb.26146

 

  1. Teng F, Zhang JX, Chen Y, et al. LncRNA NKX2-1-AS1 promotes tumor progression and angiogenesis via up-regulation of SERPINE1 expression and activation of the VEGFR-2 signaling pathway in gastric cancer. Mol Oncol. 2021;15(4):1234-1255. doi: 10.1002/1878-0261.12911

 

  1. Prabhudesai A, Shetty S, Ghosh K, Kulkarni B. Investigation of plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism in Indian venous thrombosis patients: A case-control study. Eur J Haematol. 2017;99(3):249-254. doi: 10.1111/ejh.12912

 

  1. Zhang X, Cai X, Pan J. Correlation between PAI-1 gene 4G/5G polymorphism and the risk of thrombosis in Ph chromosome-negative myeloproliferative neoplasms. Clin Appl Thromb Hemost. 2020;26:1076029620935207. doi: 10.1177/1076029620935207

 

  1. Gadomska G, Rość D, Stankowska K, Boinska J, Ruszkowska- Ciastek B, Wieczór R. Selected parameters of hemostasis in patients with myeloproliferative neoplasms. Blood Coagul Fibrinolysis. 2014;25(5):464-470. doi: 10.1097/MBC.0000000000000088

 

  1. Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer; 2017.

 

  1. Van Egeren D, Kamaz B, Liu S, et al. Transcriptional differences between JAK2-V617F and wild-type bone marrow cells in patients with myeloproliferative neoplasms. Exp Hematol. 2022;107:14-19. doi: 10.1016/j.exphem.2021.12.364

 

  1. Makukh HV, Chorna LB, Hnateyko OZ, Zastavna DV. Molecular genetic diagnosis of hereditary factors of thrombophilia: mutations g1691a of the FV gene and g20210a of the FII gene, allelic polymorphism 675 4g/5g of the PAI-1 gene. Lab Diagn. 2012;1(59):32-37. (Article in Ukrainian)

 

  1. Kubala MH, DeClerck YA. The plasminogen activator inhibitor-1 paradox in cancer: A mechanistic understanding. Cancer Metastasis Rev. 2019;38(3):483-492. doi: 10.1007/s10555-019-09806-4

 

  1. Wang J, Peng Y, Guo H, Li C. PAI-1 polymorphisms have significant associations with cancer risk, especially feminine cancer. Technol Cancer Res Treat. 2021;20:15330338211037813. doi: 10.1177/15330338211037813

 

  1. Vassalli LC, Malafaia EC, Chauffaille ML, Kerbauy D. Leukocytosis can predict thrombotic events in myelofibrosis. Blood. 2015;126(23):5191. doi: 10.1182/blood.v126.23.5191.5191

 

  1. Ohyashiki K, Kiguchi T, Ito Y, et al. Leukocytosis is linked to thrombosis at diagnosis, while JAK2 V617F mutation is associated with thrombosis during the course of essential thrombocythemia. Int J Hematol. 2008;87:446-448. doi: 10.1007/s12185-008-0080-9

 

  1. Cerutti A, Custodi P, Duranti M, Noris P, Balduini CL. Thrombopoietin levels in patients with primary and reactive thrombocytosis. Br J Haematol. 1997;99(2):281-284. doi: 10.1046/j.1365-2141.1997.3823196.x

 

  1. Koupenova M, Clancy L, Corkrey HA, Freedman JE. Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ Res. 2018;122(2):337-351. doi: 10.1161/CIRCRESAHA.117.310795

 

  1. Vannucchi AM, Barbui T. Thrombocytosis and thrombosis. Hematology. 2007;1:363-370. doi: 10.1182/asheducation-2007.1.363

 

  1. Birdane A, Haznedaroğlu IC, Bavbek N, et al. The plasma levels of prostanoids and plasminogen activator inhibitor-1 in primary and secondary thrombocytosis. Clin Appl Thromb Hemost. 2005;11(2):197-201. doi: 10.1177/107602960501100209

 

  1. Brogren H, Wallmark K, Deinum J, Karlsson L, Jern S. Platelets retain high levels of active plasminogen activator inhibitor 1. PLoS One. 2011;6(11):e26762. doi: 10.1371/journal.pone.0026762

 

  1. Corduan A, Plé H, Laffont B, et al. Dissociation of SERPINE1 mRNA from the translational repressor proteins Ago2 and TIA-1 upon platelet activation. Thromb Haemost. 2015;113(5):1046-1059. doi: 10.1160/TH14-07-0622

 

  1. Bazzan M, Tamponi G, Gallo E, et al. Fibrinolytic imbalance in essential thrombocythemia: Role of platelets. Haemostasis. 1993;23(1):38-44. doi: 10.1159/000216850

 

  1. Robbie LA, Bennett B, Croll AM, Brown PA, Booth NA. Proteins of the fibrinolytic system in human thrombi. Thromb Haemost. 1996;75(1):127-133.

 

  1. Colucci M, Semeraro N, Semeraro F. Platelets and fibrinolysis. In: Gresele P, Kleiman N, Lopez J, Page C, editors. Platelets in Thrombotic and Non-Thrombotic Disorders. Cham, Switzerland: Springer; 2017.

 

  1. Zhu Y, Carmeliet P, Fay WP. Plasminogen activator inhibitor-1 is a major determinant of arterial thrombolysis resistance. Circulation. 1999;99(23):3050-3055. doi: 10.1161/01.cir.99.23.3050

 

  1. Gieger C, Radhakrishnan A, Cvejic A, et al. New gene functions in megakaryopoiesis and platelet formation. Nature. 2011;480(7376):201-208. doi: 10.1038/nature10659

 

  1. Soranzo N, Rendon A, Gieger C, et al. A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. Blood. 2009;113(16):3831-3837. doi: 10.1182/blood-2008-10-184234

 

  1. Cotter FE, Johnson E. Chromosome 7 and haematological malignancies. Hematology. 1997;2(5):359-372. doi: 10.1080/10245332.1997.11746356

 

  1. Viny AD, Przychodzen B, O’Keefe CL et al. Various abnormalities at chromosome 7 carry distinct biologic and prognostic implications in myelodysplastic/ myeloproliferative syndromes and related marrow failures. Blood. 2010;116(21):2744-2744. doi: 10.1182/blood.v116.21.2744.2744

 

  1. Piguet PF, Vesin C, Da Laperousaz C, Rochat A. Role of plasminogen activators and urokinase receptor in platelet kinetics. Hematol J. 2000;1(3):199-205. doi: 10.1038/sj.thj.6200029

 

  1. Mejía-Ochoa M, Acevedo Toro PA, Cardona-Arias JA. Systematization of analytical studies of polycythemia vera, essential thrombocythemia and primary myelofibrosis, and a meta-analysis of the frequency of JAK2, CALR and MPL mutations: 2000–2018. BMC Cancer. 2019;19:590. doi: 10.1186/s12885-019-5764-4

 

  1. Panova-Noeva M, Marchetti M, Buoro S, et al. JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients. Blood. 2011;118:2599-2601. doi: 10.1182/blood-2011-02-339655

 

  1. Zini R, Guglielmelli P, Pietra D, et al. CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles. Blood Cancer J. 2017;7:638. doi: 10.1038/s41408-017-0010-2

 

  1. Thomas S, Krishnan A. Platelet heterogeneity in myeloproliferative neoplasms. Arterioscler Thromb Vasc Biol. 2021;41(11):2661-2670. doi: 10.1161/ATVBAHA.121.316373

 

Share
Back to top
Global Translational Medicine, Electronic ISSN: 2811-0021 Print ISSN: 3060-8600, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept