Expression of ADAM10 and CD58 in Acute and Chronic Lymphocytic Leukemia: Influence of Disease Stage and Chemotherapy

Document Type : Original Research

Authors

Department of Pathological Analyses, Faculty of Science, University of Kufa, Kufa, Najaf Governorate, Iraq

Abstract
Background & Objective: CD58 and ADAM10 have been implicated in leukemia progression and chemoresistance; however, their specific roles in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), particularly under chemotherapeutic pressure, remain insufficiently characterized. This study aimed to assess the expression of CD58, an immune adhesion molecule, and ADAM10, a metalloproteinase, in ALL and CLL patients undergoing chemotherapy, and to explore their potential involvement in immune evasion, niche-mediated survival, and chemoresistance mechanisms.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 patients with ALL, 50 with CLL, and 30 healthy controls. Expression levels of CD58 and ADAM10 were analyzed by quantitative reverse transcription PCR (qRT-PCR) and flow cytometry. Chemotherapy regimens included vincristine (VCR), methotrexate (MTX), and doxorubicin (DOXO).
Results: ADAM10 mRNA expression was significantly upregulated in ALL patients treated with VCR+MTX (p<0.0001) and DOXO (p=0.001), with corresponding protein overexpression observed in both ALL (p<0.0001) and untreated CLL patients (p<0.0001). A significant difference in ADAM10 levels was noted between ALL and CLL cohorts (p=0.001). CD58 mRNA and protein expression were markedly increased in ALL patients receiving VCR+MTX (p<0.0001), whereas untreated CLL patients exhibited no significant alterations.
Conclusion: CD58 and ADAM10 are differentially regulated in ALL under chemotherapy, supporting their roles in immune evasion and microenvironmental survival. The constitutive overexpression of ADAM10 in CLL suggests its involvement in chronic leukemic pathogenesis. These findings highlight CD58 and ADAM10 as potential therapeutic targets for overcoming chemoresistance in lymphoid malignancies.

Keywords

Subjects


Copyright © 2025. This is an open-access article distributed under the terms of the Creative Commons Attribution- 4.0 International License which permits Share, copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, even commercially.

  1. Chaimowitz NS, Martin RK, Cichy J, Gibb DR, Patil P, Kang DJ, et al. A disintegrin and metalloproteinase 10 regulates antibody production and maintenance of lymphoid architecture. J Immunol. 2011;187(10):5114-22. [DOI:10.4049/jimmunol.1102172] [PMID] [PMCID]
  2. Tosetti F, Alessio M, Poggi A, Zocchi MR. ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive Protease. Int J Mol Sci. 2021;22(9). [DOI:10.3390/ijms22094969] [PMID] [PMCID]
  3. Yang J, Zhang Z, Lam JSW, Fan H, Fu NY. Molecular Regulation and Oncogenic Functions of TSPAN8. Cells. 2024;13(2). [DOI:10.3390/cells13020193] [PMID] [PMCID]
  4. Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, et al. Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PloS one. 2009;4(8):e6613. [DOI:10.1371/journal.pone.0006613] [PMID] [PMCID]
  5. Bahrami E, Schmid JP, Jurinovic V, Becker M, Wirth AK, Ludwig R, et al. Combined proteomics and CRISPR-Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo. Mol Cancer. 2023;22(1):107. [DOI:10.1186/s12943-023-01803-0] [PMID] [PMCID]
  6. Hallek M. Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy. Am J Hematol. 2025;100(3):450-80. [DOI:10.1002/ajh.27546] [PMID] [PMCID]
  7. Veltroni M, De Zen L, Sanzari MC, Maglia O, Dworzak MN, Ratei R, et al. Expression of CD58 in normal, regenerating and leukemic bone marrow B cells: implications for the detection of minimal residual disease in acute lymphocytic leukemia. Haematologica. 2003;88(11):1245-52. [Link]
  8. Catalano M, Iannone LF, Nesi G, Nobili S, Mini E, Roviello G. Immunotherapy-related biomarkers: Confirmations and uncertainties. Crit Rev Oncol Hematol. 2023;192:104135. [DOI:10.1016/j.critrevonc.2023.104135] [PMID]
  9. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3-23. [DOI:10.1016/j.jaci.2009.12.980] [PMID] [PMCID]
  10. Xu X, Zhang Y, Lu Y, Zhang X, Zhao C, Wang J, et al. CD58 Alterations Govern Antitumor Immune Responses by Inducing PDL1 and IDO in Diffuse Large B-Cell Lymphoma. Cancer Res. 2024;84(13):2123-40. [DOI:10.1158/0008-5472.CAN-23-2874] [PMID]
  11. Shimada K, Yamaguchi M, Atsuta Y, Matsue K, Sato K, Kusumoto S, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(4):593-602. [DOI:10.1016/S1470-2045(20)30059-0] [PMID]
  12. Mohsin MI, Al-Hilali SAM, Mohsin RI, Mohasin M, Al-Shamarti MJM. IL-8/CD181 Mediated Inflammation in SLE-Associated Hemolytic Anemia. Iran J Pathol. 2025;20(2):217-24. [DOI:10.30699/ijp.2025.2051460.3403] [PMID] [PMCID]
  13. Mohsin MI, Al-Shamarti MJ, Mohsin RI, Al-Sahaf S. Role of Interleukin-36 in Response to Pseudomonas Aeruginosa Infection. Indian Journal of Forensic Medicine & Toxicology. 2020;14(3). [DOI:10.37506/ijfmt.v14i3.10545]
  14. Rosenbaum D, Saftig P. New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10). The FEBS journal. 2024;291(13):2733-66. [DOI:10.1111/febs.16870] [PMID]
  15. Clares-Pedrero I, Rocha-Mulero A, Palma-Cobo M, Cardenes B, Yanez-Mo M, Cabanas C. Molecular Determinants Involved in the Docking and Uptake of Tumor-Derived Extracellular Vesicles: Implications in Cancer. Int J Mol Sci. 2024;25(6):3449. [DOI:10.3390/ijms25063449] [PMID] [PMCID]
  16. Bahrami E, Schmid JP, Jurinovic V, Becker M, Wirth A-K, Ludwig R, et al. Combined proteomics and CRISPR-Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo. Molecular cancer. 2023;22(1):107. [DOI:10.1186/s12943-023-01803-0] [PMID] [PMCID]
  17. Moss ML, Stoeck A, Yan W, Dempsey PJ. ADAM10 as a target for anti-cancer therapy. Current pharmaceutical biotechnology. 2008;9(1):2-8. [DOI:10.2174/138920108783497613] [PMID]
  18. Sulis ML, Saftig P, Ferrando AA. Redundancy and specificity of the metalloprotease system mediating oncogenic NOTCH1 activation in T-ALL. Leukemia. 2011;25(10):1564-9. [DOI:10.1038/leu.2011.130] [PMID] [PMCID]
  19. Pagliaro L, Cerretani E, Vento F, Montanaro A, Moron Dalla Tor L, Simoncini E, Giaimo M, Gherli A, Zamponi R, Tartaglione I, Lorusso B, Scita M, Russo F, Sammarelli G, Todaro G, Silini EM, Rigolin GM, Quaini F, Cuneo A, Roti G. CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders. Int J Mol Sci. 2024 Jan 7;25(2):766. [DOI:10.3390/ijms25020766] [PMID] [PMCID]
  20. Ma S, Xu J, Wang X, Wu QY, Cao J, Li ZY, et al. [Effect of ADAM10 Inhibitor GI254023X on Proliferation and Apoptosis of Acute T-Lymphoblastic Leukemia Jurkat Cells In Vitro and Its Possible Mechanisms]. Zhongguo shi yan xue ye xue za zhi. 2015;23(4):950-5. [DOI:10.7534/j.issn.1009-2137.2015.04.008] [PMID]
  21. Lin MJ. CAR-T Bystander Killing Is Enhanced by Fas-Potentiation to Mitigate Antigen-Escape in Heterogeneous Tumors: Icahn School of Medicine at Mount Sinai; 2024. [DOI:10.1136/jitc-2024-SITC2024.0345]
  22. Abdalla AM, Miao Y, Ming N, Ouyang C. ADAM10 modulates the efficacy of T-cell-mediated therapy in solid tumors. Immunol Cell Biol. 2024;102(10):907-23. [DOI:10.1111/imcb.12826] [PMID]
  23. Feng K, Li X, Bai Y, Zhang D, Tian L. Mechanisms of cancer cell death induction by triptolide: A comprehensive overview. Heliyon. 2024;10(2):e24335. [DOI:10.1016/j.heliyon.2024.e24335] [PMID] [PMCID]
  24. Li X-M, Zhang L-P, Wang Y-Z, Lu A-D, Chang Y, Zhu H-H, et al. CD38+ CD58− is an independent adverse prognostic factor in paediatric Philadelphia chromosome negative B cell acute lymphoblastic leukaemia patients. Leukemia Research. 2016;43:33-8. [DOI:10.1016/j.leukres.2015.12.015] [PMID]
  25. Tian Z, Jia W, Wang Z, Mao H, Zhang J, Shi Q, et al. Clinical significance of immune-related antigen CD58 in gliomas and analysis of its potential core related gene clusters. Heliyon. 2024;10(8):e29275. [PMCID] [DOI:10.1016/j.heliyon.2024.e29275] [PMID]
  26. Lanier LL. NK cell receptors. Annual review of immunology. 1998;16(1):359-93. [DOI:10.1146/annurev.immunol.16.1.359] [PMID]
  27. Wu F, Xu H, Zhang B. Transcription factor KLF2 is associated with the dysfunctional status of NK cells and the prognosis of pediatric B-ALL patients. Frontiers in Oncology. 2025;14:1456004. [DOI:10.3389/fonc.2024.1456004] [PMID] [PMCID]
  28. Ishihara T, Watakabe M, Ochi S, Akisada N, Watanabe S, Ohki K, et al. A pediatric case of EBF1-PDGFRB fusion gene-positive ALL successfully treated with chemotherapy in combination with an ABL1 inhibitor. [DOI:10.1182/blood-2015-09-670166] [PMID]
  29. Naeli P, Winter T, Hackett AP, Alboushi L, Jafarnejad SM. The intricate balance between microRNA-induced mRNA decay and translational repression. FEBS J. 2023;290(10):2508-24. [DOI:10.1111/febs.16422] [PMID]
  30. Gebauer F, Hentze MW. Molecular mechanisms of translational control. Nat Rev Mol Cell Biol. 2004;5(10):827-35. [DOI:10.1038/nrm1488] [PMID] []
  31. Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life. Embo J. 1998;17(24):7151-60. [DOI:10.1093/emboj/17.24.7151] [PMID] [PMCID]
  32. Kimby E, Rincón J, Patarroyo M, Mellstedt H. Expression of Adhesion Molecules CD 11/CD 18 (Leu-CAMs, β2-Integrins), CD54 (ICAM-1) and CD58 (LFA-3) in B-Chronic Lymphocytic Leukemia. Leukemia & Lymphoma. 1994;13(3-4):297-306. [DOI:10.3109/10428199409056294] [PMID]
Volume 20, Issue 3
Summer 2025
Pages 316-325

  • Receive Date 14 April 2025
  • Revise Date 12 June 2025
  • Accept Date 28 June 2025