International Journal of Genetics and Genomics
Volume 5, Issue 5, October 2017, Pages: 49-53
Received: Feb. 27, 2017;
Accepted: Apr. 21, 2017;
Published: Oct. 18, 2017
Views 3172 Downloads 186
Anas Abdelrahman Ibrahim, Department of Hematology & Immunohematology, Faculty of Medical Laboratory Sciences, Omdurman Islamic University, Khartoum, Sudan
Eltahir Awad Gasim Khalil, Department of Clinical Pathology & Immunology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan
Transformation of myeloproliferative disorders (MPDs) to acute leukemia is an evitable event that represents a stumbling block in the management of patients. The Janus Kinase-2 JAK2V617F mutation of MDP does not clarify the phenotypic variability observed in this disorder. But, a mutations in Ten-eleven-translocation-2 (TET2), a putative tumor suppressor gene, was recently implicated in MPDs and other hematologic malignancies. TET-2 is believed to play a role in leukemic transformation. This study aimed to determine the frequency of L1721W polymorphism in TET2 gene in a cohort of Sudanese patients with MPDs. Following informed consent, 25 (25/50, 50%) patients with polycythemia rubra vera (PRV), thirteen patients (13/50, 26%) with essential thrombocythemia (ET), eleven patients (11/50, 22%) with chronic myeloid leukemia (CML), and one patient (1/50, 2%) with primary myelofibrosis (PMF) were enrolled. None of the patients was in the transformation phase. Patients were diagnosed based on clinical picture, hematological parameters and JAK2V617F and BCR_ABL molecular aberrations. JAK2V617F was detected in Ph-negative-MPDs cases as (24/25, 96%) in PRV, (10/13, 76%) in ET, and (1/1, 100%) in PMF. BCR_ABL fusion was detected in all (11/11, 100%) cases of CML. DNA was extracted using the guanidine chloride method, followed by (PCR-RFLP) analysis. Only one patient showed the presence of L1721W polymorphism of the TET2. It was inferred that the low frequency of this transformation within the study cohort [all in chronic phase] probably indicates that it plays a minor role in MPD pathogenesis, while its role in blast transformation needs further studies in MPD patients.
Anas Abdelrahman Ibrahim,
Eltahir Awad Gasim Khalil,
Frequency of L1721W Polymorphism in TET2 Gene Among a Cohort of Sudanese Patients with Myeloproliferative Disorders: Possible Roles in Pathogenicity and Leukemic Transformation, International Journal of Genetics and Genomics.
Vol. 5, No. 5,
2017, pp. 49-53.
Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951; 6(4): 372-375.
Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM (1999). The biology of chronic myeloid leukemia. New England Journal of Medicine 341: 164-172.
Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, Wheatley K, Burnett AK, Goldstone AH. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001; 98(5): 1312-1320.
Larson RA. Is secondary leukemia an independent poor prognostic factor in acute myeloid leukemia. Best Pract Res Clin Haematol.2007; 20(1): 29-37.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myeloﬁbrosis. Cancer Cell. 2005; 7(4): 387-397.
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352(17): 1779-1790.
Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009; 114(1): 144-147.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324(5929): 930-5.
Pastor, W. A., Aravind, L. & Rao, A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol. 14, 341–356 (2013).
Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C, Münzel M, Wagner M, Müller M, Khan F, Eberl HC, Mensinga A, Brinkman AB, Lephikov K, Müller U, Walter J, Boelens R, van Ingen H, Leonhardt H, Carell T, Vermeulen M. Dynamic readers for 5-(hydroxy) methylcytosine and its oxidized derivatives. Cell 152, 1146–1159 (2013).
Wu, H. & Zhang, Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156, 45–68 (2014).
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lécluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Bernard OA. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009; 360(22): 2289-2301.
An J, González-Avalos E, Chawla A, Jeong M, López-Moyado IF, Li W, Goodell MA, Chavez L, Ko M, Rao A. Acute loss of TETfunction results in aggressive myeloid cancer in mice. Nature Communications. 2015; 6: 10071. doi: 10.1038/ncomms10071.
Langemeijer SMC, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, Van Hoogen P, Van Kessel AG, Raymakers RAP, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, De Witte T, Van Der Reijden BA, Jansen JH. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nature Genetics. 41(7): 838-842.
Nibourel O, Kosmider O, Cheok M, Boissel N, Renneville A, Philippe N, Dombret H, Dreyfus F, Quesnel B, Geffroy S, Quentin S, Roche-Lestienne C, Cayuela J, Roumier C, Fenaux P, Vainchenker W, Bernard OA, Soulier J, Fontenay M, Preudhomme C. Incidence and prognostic value of TET2 alterations in de novo acute myeloid leukemia achieving complete remission. Blood. 116: 1132-1135.
Martinez-Avilés L, Besses C, Alvarez-Larran, Torres E, Serrano S, Bellosillo B. TET2, ASXL1, IDH1, IDH2 and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Annals of Hematology. 91: 533-541.
Tefferi and J. M. Vardiman, “Classification and Diagnosis of Myeloproliferative Neoplasms: The 2008 World Health Organization Criteria and Point-of-Care Diagnostic Algorithms,” Leukemia, Vol. 22, 2008, pp. 14-22.
Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classificationof the myeloid neoplasms. Blood. 2002; 100(7): 2292-2302.
Pardanani A, Reeder TL, Kimlinger TK, Baek JY, Li CY, Butterfield JH, Tefferi A. Flt-3 and c-kit mutation studies in a spectrum of chronic myeloid disorders including systemic mast cell disease. Leuk Res. 2003; 27:739–742.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464): 1054-1061. 22: 756–761.
G. W. Montgomerya & J. A. Sisea. Extraction of DNA from sheep white blood cells. New Zealand Journal of Agricultural Research. 2012; 33; 437-441.