Activation-Induced Cytidine Deaminase Expression in Patients with Chronic Myeloid Leukemia

Year 2022, , 155 - 159, 31.12.2022

Emin Oguz , Aynur Dağlar Aday , Akif Selim Yavuz

https://doi.org/10.26650/experimed.1193401

Abstract

Objective: The findings on chronic myeloid leukemia (CML) patients suggest that clonal tumoral cells tend to have additional mutations besides the formation of the BCR-ABL fusion gene. Previous studies have demonstrated abnormal activation-induced cytidine deaminase (AID) expression in various types of cancer, showing AID transcript levels to be elevated in the CML blast phase. The study aimed to investigate the AID gene expression levels in CML and to investigate the etiopathogenic role of AID, which is not yet fully understood.

Materials and Methods: This study analyzed the AID transcript levels of 80 CML patients and 50 controls using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR).

Results: The study found the AID transcript levels to be significantly elevated (p < 0.001) in the CML patients compared to the control group, with no significance in AID transcript levels with regard to the patients’ age, gender, clinical characteristics, or laboratory findings. No correlation was found between the AID and BCR-ABL transcript levels, while a positive correlation was present between AID transcript levels and presence of polymorphonuclear leukocytes (PMNL; r = 0.320, p = 0.021). No significant relationship occurred in AID transcription levels with the tyrosine-kinase-inhibitor (TKI) resistant mutation profile or cytogenetic response during TKI therapy.

Conclusion: This study found AID expression levels to be significantly elevated in CML patients and AID to be able to contribute to the etiopathogenesis of CML

Keywords

Chronic myeloid leukemia, gene expression, cytidine deaminase

Project Number

40224

References

• 1. Chereda B, Melo JV. Natural course and biology of CML. Ann Hematol 2015; 94(Suppl 2): S107-21. [CrossRef] google scholar
• 2. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000; 102(5): 553-63. [CrossRef] google scholar
• 3. Conticello SG. The AID/APOBEC family of nucleic acid mutators. Genome Biol 2008; 9(6): 229. [CrossRef] google scholar
• 4. Sablitzky F, Wildner G, Rajewsky K. Somatic mutation and clonal expansion of B cells in an antigen-driven immune response. EMBO J 1985; 4(2): 345-50. [CrossRef] google scholar
• 5. Rios LAS, Cloete B, Mowla S. Activation-induced cytidine deaminase: in sickness and in health. J Cancer Res Clin Oncol 2020; 146(11): 2721-30. [CrossRef] google scholar
• 6. Hu D, Zheng H, Liu H, Li M, Ren W, Liao W, et al. Immunoglobulin expression and its biological significance in cancer cells. Cell Mol Immunol 2008; 5(5): 319-24. [CrossRef] google scholar
• 7. Kunimoto H, McKenney AS, Meydan C, Shank K, Nazir A, Rapaport F, et al. Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells. Blood 2017; 129(13): 1779-90. [CrossRef] google scholar
• 8. Yu K, Huang FT, Lieber MR. DNA substrate length and surrounding sequence affect the activation-induced deaminase activity at cytidine. J Biol Chem 2004; 279(8): 6496-500. [CrossRef] google scholar
• 9. Chen Z, Qiu X, Gu J. Immunoglobulin expression in non-lymphoid lineage and neoplastic cells. Am J Pathol 2009; 174(4): 1139-48. [CrossRef] google scholar
• 10. Dominguez PM, Shaknovich R. Epigenetic function of activation-induced cytidine deaminase and its link to lymphomagenesis. Front Immunol 2014; 5: 642. [CrossRef] google scholar
• 11. Feldhahn N, Henke N, Melchior K, Duy C, Soh BN, Klein F, et al. Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells. J Exp Med 2007; 204(5): 1157-66. [CrossRef] google scholar
• 12. Maura F, Rustad EH, Yellapantula V,tuksza M, Hoyos D, Maclachlan KH, et al. Role of AID in the temporal pattern of acquisition of driver mutations in multiple myeloma. Leukemia 2020; 34(5): 1476-80. [CrossRef] google scholar
• 13. Rebhandl S, Huemer M, Greil R, Geisberger R. AID/APOBEC deaminases and cancer. Oncoscience 2015; 2(4): 320-33. [CrossRef] google scholar
• 14. Torun ES, Dağlar Aday A, Nalçaci M. Activation-induced cytidine deaminase expression in patients with myelodysplastic syndrome and its relationship with prognosis and treatment. Turk J Med Sci 2021; 51(5): 2451-60. [CrossRef] google scholar
• 15. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008; 22(1): 14-22. [CrossRef] google scholar
• 16. World Medical Association. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 2013; 310(20): 2191-4. [CrossRef] google scholar
• 17. Dermenci H, Daglar Aday A, Akadam Teker AB, Hancer V, Gelmez MY, Nalcaci M, et al. Aberrant activation-induced cytidine deaminase gene expression links BCR/ABL1-negative classical myeloproliferative neoplasms. Med Bull Haseki 2022; 60: 228-33. [CrossRef] google scholar
• 18. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005; 5(3): 172-83. [CrossRef] google scholar
• 19. Ochi Y, Yoshida K, Huang YJ, Kuo MC, Nannya Y, Sasaki K, et al. Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia. Nat Commun 2021; 12(1): 2833. [CrossRef] google scholar
• 20. Maiti A, Franquiz MJ, Ravandi F, Cortes JE, Jabbour EJ, Sasaki K, et al. Venetoclax and BCR-ABL tyrosine kinase inhibitor combinations: outcome in patients with philadelphia chromosome-positive advanced myeloid leukemias. Acta Haematol 2020; 143(6): 56773. [CrossRef] google scholar
• 21. Okazaki IM, Hiai H, Kakazu N, Yamada S, Muramatsu M, Kinoshita K, et al. Constitutive expression of AID leads to tumorigenesis. J Exp Med 2003; 197(9): 1173-81. [CrossRef] google scholar
• 22. Pasqualucci L, Bhagat G, Jankovic M, Compagno M, Smith P, Muramatsu M, et al. AID is required for germinal center-derived lymphomagenesis. Nat Genet 2008; 40(1): 108-12. [CrossRef] google scholar
• 23. Robbiani DF, Bunting S, Feldhahn N, Bothmer A, Camps J, Deroubaix S, et al. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol Cell 2009; 36(4): 631-41. [CrossRef] google scholar
• 24. Klemm L, Duy C, Iacobucci I, Kuchen S, von Levetzow G, Feldhahn N, et al. The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia. Cancer Cell 2009; 16(3): 232-45. [CrossRef] google scholar
• 25. Muñoz DP, Lee EL, Takayama S, Coppé JP, Heo SJ, Boffelli D, et al. Activation-induced cytidine deaminase (AID) is necessary for the epithelial-mesenchymal transition in mammary epithelial cells. Proc Natl Acad Sci USA 2013; 110(32): E2977-86. [CrossRef] google scholar
• 26. Godsmark G, DE Souza Rios LA, Mowla S. Activation-induced cytidine deaminase promotes proliferation and enhances chemoresistance and migration in B-cell lymphoma. Anticancer Res 2021; 41(1): 237-47. [CrossRef] google scholar
• 27. Hancer VS, Kose M, Diz-Kucukkaya R, Yavuz AS, Aktan M. Activation-induced cytidine deaminase mRNA levels in chronic lymphocytic leukemia. Leuk Lymphoma 2011; 52(1): 79-84. [CrossRef] google scholar
• 28. Liu Z, Wu X, Duan Y, Wang Y, Shan B, Kong J, et al. AID expression is correlated with Bcr-Abl expression in CML-LBC and can be down-regulated by As2O3 and/or imatinib. Leuk Res 2011; 35(10): 13559. [CrossRef] google scholar
• 29. Gruber TA, Chang MS, Sposto R, Müschen M. Activation-induced cytidine deaminase accelerates clonal evolution in BCR-ABL1-driven B-cell lineage acute lymphoblastic leukemia. Cancer Res 2010; 70(19): 7411-20. [CrossRef] google scholar
• 30. Zingde S. The neutrophil in chronic myeloid leukaemia: Molecular analysis of chemotaxis, endocytosis and adhesion. Cancer J 1998; 11: 167-75. google scholar