Study of Tumor Necrosis Factor-Alpha-Induced Protein 3 Gene Single-Nucleotide Variants in JAK2 V617F-Positive Myeloproliferative Disorders: A Case–Control Study

Wafaa M. Abdelghany; Noha M. El Husseiny; Gehad H. Fekry; Osama H. Korayem; Rehab Helmy

doi:10.3889/oamjms.2022.7934

Authors

Wafaa M. Abdelghany Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
Noha M. El Husseiny Department of Clinical Hematology
Gehad H. Fekry Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Osama H. Korayem Department of Biotechnology and Life Sciences, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef, Egypt https://orcid.org/0000-0001-7793-2760
Rehab Helmy Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt

DOI:

https://doi.org/10.3889/oamjms.2022.7934

Keywords:

TNFAIP3, MPNs, JAK2, Incidence, Prognosis

Abstract

Background and Objectives: Myeloproliferative neoplasms (MPNs) are Philadelphia negative disorders involving polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF). Although JAK2 mutation is almost involved, other several mutations are linked to MPNs risk and prognosis. TNFAIP3 genetic mutations are related to several cancers and autoimmune diseases. Our study aimed to demonstrate the effects of rs2230926_T/G & rs5029939_C/G SNVs of TNFAIP3 gene on the risk and prognosis of JAK2 V617F positive MPNs.

Methods: Matched 2 groups in age, sex and race were enrolled in our research; 80 MPNs cases group and 130 normal healthy controls group with follow up of MPNs cases for 3 years. Taqman assay probes involved in real time polymerase chain reaction (PCR) were utilized for variants analysis.

Results: The rs2230926 & rs5029939 SNVs were in modest linkage disequilibrium (LD) in MPNs cases. The observed frequencies of G allele and its genotypes of both variants were more prevalent in MPNs patients than normal controls. The bleeding symptoms and the presence of splenomegaly were more existent in the heterozygous genotype and the combined G involved genotypes respectively. The overall survival (OS) was lower in G containing genotypes of both variants but the progression free survival (PFS) was affected only in rs5029939 SNV.

Conclusion: Our study revealed the association of G containing genotypes of both rs2230926 & rs5029939 SNVs to the increased MPNs incidence as well to poor clinical course and prognosis of JAK2 V617F positive MPNs disorders in Egyptian ethnic.

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References

Chen Y, Fang F, Hu Y, Liu Q, Bu D, Tan M, et al. The polymorphisms in LNK gene correlated to the clinical type of myeloproliferative neoplasms. PLoS One. 2016;11(4):e0154183. https://doi.org/10.1371/journal.pone.0154183 PMid:27111338 DOI: https://doi.org/10.1371/journal.pone.0154183

Passamonti F, Maffioli M. Update from the latest WHO classification of MPNs: A user’s manual. Hematology Am Soc Hematol Educ Program. 2016;2016(1):534-42. https://doi.org/10.1182/asheducation-2016.1.534 PMid:27913526 DOI: https://doi.org/10.1182/asheducation-2016.1.534

Uras IZ, Maurer B, Nivarthi H, Jodl P, Kollmann K, Prchal- Murphy M, et al. CDK6 coordinates JAK2V617F mutant MPN via NF-κB and apoptotic networks. Blood. 2019;133(15):1677-90. https://doi.org/10.1182/blood-2018-08-872648 PMid:30635286 DOI: https://doi.org/10.1182/blood-2018-08-872648

Fisher DA, Malkova O, Engle EK, Miner CA, Fulbright MC, Behbehani GK, et al. Mass cytometry analysis reveals hyperactive NF kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. Leukemia. 2017;31(9):1962-74. https://doi.org/10.1038/leu.2016.377 PMid:28008177 DOI: https://doi.org/10.1038/leu.2016.377

Zhu L, Zhang F, Shen Q, Chen S, Wang X, Wang L, et al. Characteristics of A20 gene polymorphisms in T-cell acute lymphocytic leukemia. Hematology. 2014;19(8):448-54. https://doi.org/10.1179/1607845414Y.0000000160 PMid:24611736 DOI: https://doi.org/10.1179/1607845414Y.0000000160

Park MH, Hong JT. Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches. Cells. 2016;5(2):15. https://doi.org/10.3390/cells5020015 PMid:27043634 DOI: https://doi.org/10.3390/cells5020015

Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010;17(1):13-27. https://doi.org/10.1016/j.ccr.2009.11.020 PMid:20060365 DOI: https://doi.org/10.1016/j.ccr.2009.11.020

Grosjean-Raillard J, Tailler M, Ades L, Perfettini JL, Fabre C, Braun T, et al. ATM mediates constitutive NF-kappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene. 2009;28(8):1099-109. https://doi.org/10.1038/onc.2008.457 PMid:19079347 DOI: https://doi.org/10.1038/onc.2008.457

Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459(7247):712-6. https://doi.org/10.1038/nature07969 PMid:19412163 DOI: https://doi.org/10.1038/nature07969

Braun FC, Grabarczyk P, Möbs M, Braun FK, Eberle J, Beyer M, et al. Tumor suppressor TNFAIP3 (A20) is frequently, deleted in Sézary syndrome. Leukemia. 2011;25(9):1494-501. https://doi.org/10.1038/leu.2011.101 PMid:21625233 DOI: https://doi.org/10.1038/leu.2011.101

Bates JS, Lessard CJ, Leon JM, Nguyen T, Battiest LJ, Rodgers J, et al. Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations. Genes Immun. 2009;10(5):470-7. https://doi.org/10.1038/gene.2009.31 PMid:19387456 DOI: https://doi.org/10.1038/gene.2009.31

Kim SY, Bae SH, Bang SM, Ki-Seong Eom KS, Hong J, Jang S, et al. The 2020 revision of the guidelines for the management of myeloproliferative neoplasms. Korean J Intern Med. 2021;36(1):45-62. https://doi.org/10.3904/kjim.2020.319 PMid:33147902 DOI: https://doi.org/10.3904/kjim.2020.319

Alvarez-Larrán A, Besses C. Antiplatelet therapy in the management of myeloproliferative neoplasms. Curr Hematol Malig Rep. 2014;9(4):319-23. https://doi.org/10.1007/s11899-014-0226-1 PMid:25120015 DOI: https://doi.org/10.1007/s11899-014-0226-1

Zapata C. Linkage disequilibrium measures for fine-scale mapping of disease loci are revisited. Front Genet. 2013;4:228. https://doi.org/10.3389/fgene.2013.00228 PMid:24204380 DOI: https://doi.org/10.3389/fgene.2013.00228

Berger S, Schlather M, de los Campos G, Weigend S, Preisinger R, Erbe M, et al. A scale-corrected comparison of linkage disequilibrium levels between genic and non-genic regions. PLoS One. 2015;10(10):e0141216. https://doi.org/10.1371/journal.pone.0141216 PMid:26517830 DOI: https://doi.org/10.1371/journal.pone.0141216

Skov V, Riley C, Thomassen M, Kjær L, Larsen TS, Bjerrum OW, et al. Interferon-alfa2 treatment of patients with polycythemia vera and related neoplasms influences deregulated inflammation and immune genes in polycythemia vera and allied neoplasms. Blood. 2018;132(1):5490. https://doi.org/10.1182/blood-2018-99-118690 DOI: https://doi.org/10.1182/blood-2018-99-118690

Fisher DA, Fowles JS, Zhou A, Oh ST. Inflammatory pathophysiology as a contributor to myeloproliferative neoplasms. Front Immunol. 2021;12:683401. https://doi.org/10.3389/fimmu.2021.683401 PMid:34140953 DOI: https://doi.org/10.3389/fimmu.2021.683401

Zhou H, Yang J, Liu L, Zhang D, Zhou K, Li H, et al. The polymorphisms of tumor necrosis factor-induced protein 3 gene may contribute to the susceptibility of chronic primary immune thrombocytopenia in Chinese population. Platelets. 2016;27(1):26-31. https://doi.org/10.3109/09537104.2015.1022142 PMid:25806576 DOI: https://doi.org/10.3109/09537104.2015.1022142

Zhou J, Ching YQ, Chng WJ. Aberrant nuclear factor-kappa B activity in acute myeloid leukemia: From molecular pathogenesis to therapeutic target. Oncotarget. 2015;6(8):5490-500. https://doi.org/10.18632/oncotarget.3545 PMid:25823927 DOI: https://doi.org/10.18632/oncotarget.3545

Fisher DA, Miner CA, Engle EK, Hu H, Collins TB, Zhou A, et al. Cytokine production in myelofibrosis exhibits differential responsiveness to JAKSTAT, MAP kinase, and NFkappaB signaling. Leukemia. 2019;33(8):1978-95. https://doi.org/10.1038/s41375-019-0379-y PMid:30718771 DOI: https://doi.org/10.1038/s41375-019-0379-y

Kleppe M, Koche R, Zou L, van Galen P, Hill CE, Dong L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2017;21:489-501. https://doi.org/10.1016/j.ccell.2017.11.009 PMid:29249691 DOI: https://doi.org/10.1016/j.ccell.2017.11.009

Jacquelin S, Straube J, Cooper L, Vu T, Song A, Bywater M, et al. Jak2V617F and dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation. Blood. 2018;132(26):2707-21. https://doi.org/10.1182/blood-2018-04-846220 PMid:30366920 DOI: https://doi.org/10.1182/blood-2018-04-846220

Musone SL, Taylor KE, Nititham J, Chu C, Poon A, Liao W, et al. Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. Genes Immun. 2011;12(3):176-82. https://doi.org/10.1038/gene.2010.64 PMid:21326317 DOI: https://doi.org/10.1038/gene.2010.64

Zanaty MI, Korayem OH, Meabed MH, El Demerdash D, Abdelghany WM. Impact of TNFAIP3 genetic polymorphisms on primary immune thrombocytopenia in Egyptian adult: Case-control study. Open Access Maced J Med Sci. 2021. DOI: https://doi.org/10.21203/rs.3.rs-205009/v1

Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FW, Jansen AJ. Emerging concepts in immune thrombocytopenia. Front Immunol. 2018;9:880. https://doi.org/10.3389/fimmu.2018.00880 PMid:29760702 DOI: https://doi.org/10.3389/fimmu.2018.00880

Broen JCA, Coenen MJ, Radstake TR. Genetics of systemic sclerosis: An update. Curr Rheumatol Rep. 2012;14(1):11-21. https://doi.org/10.1007/s11926-011-0221-7 PMid:22102179 DOI: https://doi.org/10.1007/s11926-011-0221-7