TETRASPANIN CD9 AND CD81: DIFFERENTIAL REGULATION AND POTENTIAL ROLES IN CHEMORESISTANCE IN ACUTE AND CHRONIC LYMPHOCYTIC LEUKEMIA



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Abstract

Abstract

Tetraspanins (TSPANs) are a family of transmembrane proteins implicated in diverse cellular processes, including signal transduction and cell adhesion.  While their precise functions are still being elucidated, their involvement in cancer, particularly leukemia, is increasingly recognized. This study focuses on the multifaceted roles of two specific TSPANs, CD9 and CD81, in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), with a specific emphasis on their impact on chemotherapy response.  Previous research has established CD9 as a prognostic marker in B-cell ALL (B-ALL), with expression correlating with specific genetic subtypes and glucocorticoid resistance.  However, its role in other leukemia subtypes and its precise contribution to chemoresistance remain incompletely understood.  Similarly, CD81 has been shown to mediate chemoresistance in B-ALL by facilitating protective interactions with the bone marrow microenvironment, but its significance in CLL and its broader impact on chemotherapy sensitivity require further investigation.  This study addresses these gaps by investigating the expression of CD9 and CD81 in ALL and CLL patients, stratified by chemotherapy regimen, including vincristine (VCR), methotrexate (MTX), and doxorubicin (DOXO).  Our results demonstrate a statistically significant upregulation of both CD9 and CD81 at the gene and protein levels in ALL patients treated with chemotherapy compared to controls.  Furthermore, we observed significant upregulation of CD9 in untreated CLL patients, while no significant difference in CD9 or CD81 expression was found between the ALL and CLL groups.  These findings strongly suggest a critical role for CD9 and CD81 in mediating chemoresistance in ALL, particularly in the context of VCR, MTX, and DOXO treatment.  Based on these observations, we discuss potential mechanisms by which CD9 and CD81 contribute to leukemogenesis and propose that targeting these TSPANs may represent a novel therapeutic strategy to overcome chemoresistance and improve patient outcomes in leukemia.

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About the authors

Ameer Hamid Khadim

University of Kufa

Email: amiralgnabe90@gmail.com
ORCID iD: 0009-0009-2088-365X

Ameer Hamid Kadhim Al-gnabi, MSc Department of Pathological Analyses, Faculty of Science, University of Kufa, Kufa, Najaf Governorate, Iraq

Iraq

Muslim Idan Mohsin

University of Kufa

Author for correspondence.
Email: muslim.aljabri@uokufa.edu.iq
ORCID iD: 0000-0002-8276-0825

Muslim Idan Mohsin, PhD, Assistant Professor, Department of Pathological Analyses, Faculty of Science, University of Kufa, Kufa, Najaf Governorate, Iraq

Iraq

References

  1. Leung KT, Cai J, Liu Y, Chan KYY, Shao J, Yang H, et al. Prognostic implications of CD9 in childhood acute lymphoblastic leukemia: insights from a nationwide multicenter study in China. Leukemia. 2024;38(2):250-7. Leung KT, Cai J, Liu Y, Chan KYY, Shao J, Yang H, et al. Prognostic implications of CD9 in childhood acute lymphoblastic leukemia: insights from a nationwide multicenter study in China. Leukemia. 2024;38(2):250-7. https://doi.org/10.1038/s41375-023-02106-w
  2. Liang P, Miao M, Liu Z, Wang H, Jiang W, Ma S, et al. CD9 expression indicates a poor outcome in acute lymphoblastic leukemia. Cancer Biomarkers. 2018;21(4):781-6. Liang P, Miao M, Liu Z, Wang H, Jiang W, Ma S, et al. CD9 expression indicates a poor outcome in acute lymphoblastic leukemia. Cancer Biomarkers. 2018;21(4):781-6. https://doi.org/10.3233/CBM-181512
  3. Koh HM, Jang BG, Lee DH, Hyun CL. Increased CD9 expression predicts favorable prognosis in human cancers: a systematic review and meta-analysis. Cancer cell international. 2021;21:1-13. Koh HM, Jang BG, Lee DH, Hyun CL. Increased CD9 expression predicts favorable prognosis in human cancers: a systematic review and meta-analysis. Cancer cell international. 2021;21:1-13. https://doi.org/10.1186/s12935-021-02058-2
  4. Zhang C, Chan KYY, Ng WH, Cheung JTK, Sun Q, Wang H, et al. CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia. Haematologica. 2024;109(9):2833. Zhang C, Chan KYY, Ng WH, Cheung JTK, Sun Q, Wang H, et al. CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia. Haematologica. 2024;109(9):2833. https://doi.org/10.3324/haematol.2023.283182
  5. Qiu K-y, Huang L-B, Mai H-R, Li X-y, Tang Y-L, He Y-y, et al. Benefits of the Continuous Use of 6-MP/MTX with Pulses of VCR/DEX in Maintenance Therapy for Pediatric Acute Lymphoblastic Leukemia: A Report from South China Children's Leukemia Group. Qiu K-y, Huang L-B, Mai H-R, Li X-y, Tang Y-L, He Y-y, et al. Benefits of the Continuous Use of 6-MP/MTX with Pulses of VCR/DEX in Maintenance Therapy for Pediatric Acute Lymphoblastic Leukemia: A Report from South China Children's Leukemia Group. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4853279
  6. Johnson-Arbor K, Dubey R. Doxorubicin. 2017. Johnson-Arbor K, Dubey R. Doxorubicin. 2017. https://europepmc.org/article/nbk/nbk459232
  7. Muzzafar T, Medeiros LJ, Wang SA, Brahmandam A, Thomas DA, Jorgensen JL. Aberrant underexpression of CD81 in precursor B-cell acute lymphoblastic leukemia: utility in detection of minimal residual disease by flow cytometry. American journal of clinical pathology. 2009;132(5):692-8. Muzzafar T, Medeiros LJ, Wang SA, Brahmandam A, Thomas DA, Jorgensen JL. Aberrant underexpression of CD81 in precursor B-cell acute lymphoblastic leukemia: utility in detection of minimal residual disease by flow cytometry. American journal of clinical pathology. 2009;132(5):692-8. https://doi.org/10.1309/AJCP4387Q864D396
  8. Quagliano A, Gopalakrishnapillai A, Kolb EA, Barwe SP. CD81 knockout promotes chemosensitivity and disrupts in vivo homing and engraftment in acute lymphoblastic leukemia. Blood advances. 2020;4(18):4393-405. Quagliano A, Gopalakrishnapillai A, Kolb EA, Barwe SP. CD81 knockout promotes chemosensitivity and disrupts in vivo homing and engraftment in acute lymphoblastic leukemia. Blood advances. 2020;4(18):4393-405. https://doi.org/10.1182/bloodadvances.2020002167
  9. Afacan-Öztürk HB, Falay M, Albayrak M, Yıldız A, Öztürk ҪP, Maral S, et al. CD81 expression in the differential diagnosis of chronic lymphocytic leukemia. Clin Lab. 2019;65(3):802-13. Afacan-Öztürk HB, Falay M, Albayrak M, Yıldız A, Öztürk ҪP, Maral S, et al. CD81 expression in the differential diagnosis of chronic lymphocytic leukemia. Clin Lab. 2019;65(3):802-13. https://doi.org/10.7754/Clin.Lab.2018.181016
  10. 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). 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
  11. Ni Y, Zhou X, Yang J, Shi H, Li H, Zhao X, et al. The role of tumor-stroma interactions in drug resistance within tumor microenvironment. Frontiers in cell and developmental biology. 2021;9:637675. Thapa RK, Nguyen HT, Jeong J-H, Kim JR, Choi H-G, Yong CS, et al. Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. Scientific reports. 2017;7(1):43299. Ni Y, Zhou X, Yang J, Shi H, Li H, Zhao X, et al. The role of tumor-stroma interactions in drug resistance within tumor microenvironment. Frontiers in cell and developmental biology. 2021;9:637675. https://doi.org/10.3389/fcell.2021.637675
  12. Thapa RK, Nguyen HT, Jeong J-H, Kim JR, Choi H-G, Yong CS, et al. Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. Scientific reports. 2017;7(1):43299. Thapa RK, Nguyen HT, Jeong J-H, Kim JR, Choi H- https://www.nature.com/articles/srep43299
  13. Ullah M, Akbar A, Ng NN, Concepcion W, Thakor AS. Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism. Oncotarget. 2019;10(37):3435. Ullah M, Akbar A, Ng NN, Concepcion W, Thakor AS. Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism. Oncotarget. 2019;10(37):3435. https://doi.org/10.18632/oncotarget.26952
  14. Havas AP. Defining mechanisms of sensitivity and resistance to histone deacetylase inhibitors to develop effective therapeutic strategies for the treatment of aggressive diffuse large B-cell lymphoma: The University of Arizona; 2016. Havas AP. Defining mechanisms of sensitivity and resistance to histone deacetylase inhibitors to develop effective therapeutic strategies for the treatment of aggressive diffuse large B-cell lymphoma: The University of Arizona; 2016. https://www.proquest.com/openview/8600615e78a266f73170d9ee4f2bb017/1?pq-origsite=gscholar&cbl=18750
  15. Gurashi K. A Multi-Omic Investigation of Molecular Pathogenesis, Cellular Phenotypes, and Therapeutic Vulnerabilities of Blast Phase Chronic Myelomonocytic Leukaemia: The University of Manchester (United Kingdom); 2023. Gurashi K. A Multi-Omic Investigation of Molecular Pathogenesis, Cellular Phenotypes, and Therapeutic Vulnerabilities of Blast Phase Chronic Myelomonocytic Leukaemia: The University of Manchester (United Kingdom); 2023. https://www.proquest.com/openview/2691929abb5776c0f1427943daacfcc9/1?pq-origsite=gscholar&cbl=2026366&diss=y
  16. Kwok MCK. Novel insights into the clinical heterogeneity and treatment of chronic lymphocytic leukaemia: University of Birmingham; 2018. Kwok MCK. Novel insights into the clinical heterogeneity and treatment of chronic lymphocytic leukaemia: University of Birmingham; 2018. http://etheses.bham.ac.uk/id/eprint/8560
  17. Chen L, Liu S, Tao Y. Regulating tumor suppressor genes: post-translational modifications. Signal transduction and targeted therapy. 2020;5(1):90. Chen L, Liu S, Tao Y. Regulating tumor suppressor genes: post-translational modifications. Signal transduction and targeted therapy. 2020;5(1):90. https://www.nature.com/articles/s41392-020-0196-9
  18. Lagou MK, Anastasiadou DP, Karagiannis GS. A proposed link between acute thymic involution and late adverse effects of chemotherapy. Frontiers in immunology. 2022;13:933547. Lagou MK, Anastasiadou DP, Karagiannis GS. A proposed link between acute thymic involution and late adverse effects of chemotherapy. Frontiers in immunology. 2022;13:933547. https://doi.org/10.3389/fimmu.2022.933547

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