Russian Journal of ImmunologyRussian Journal of ImmunologyРоссийский иммунологический журнал1028-72212782-7291Russian Society of Immunology1736210.46235/1028-7221-17362-IRAORIGINAL ARTICLESОРИГИНАЛЬНЫЕ СТАТЬИUnknownIL-1RAP AND CD26 DYNAMICS IN MYELOID MALIGNANCIES: IMPLICATIONS FOR CHEMORESISTANCE AND THERAPEUTIC RESPONSEhttps://orcid.org/0009-0006-9170-9593AL-ZobaidyMortada Hamed
Iraq

MSc;

Department of Anesthesia, College of Medical Technique, The Islamic University

Mortadah033@gmail.comAl-DahhanHawraa Abdulmeer Ali
Iraq

PhD, Professor;

University of Kufa, Faculty of science, Pathological laboratory analysis Department

hawraa.aldahan@uokufa.edu.iqThe Islamic UniversityUniversity of Kufa050220262712202518012026Copyright ©; , AL-Zobaidy M.H., Al-Dahhan H.A.Copyright ©; , AL-Zobaidy M., Al-Dahhan H.AL-Zobaidy M.H., Al-Dahhan H.A.AL-Zobaidy M., Al-Dahhan H.https://creativecommons.org/licenses/by/4.0https://rusimmun.ru/jour/article/view/17362

Background: IL-1 receptor accessory protein (IL-1RAP) and CD26 drive leukemogenesis in acute and chronic myeloid leukemia (AML/CML) by supporting leukemic stem cell (LSC) survival, immune evasion, and chemoresistance. This study evaluates their expression dynamics post-chemotherapy to elucidate therapeutic implications.

Methods: Blood samples were collected from 130 individuals, including 50 AML patients (mean age: 65), 50 CML patients (64), and 30 healthy controls (46) at Al-Forat Al-Awsat Hospital (Iraq) from May 1st, 2024, to March 2nd, 2025. IL-1RAP and CD26 mRNA were quantified via qRT-PCR, and IL-1RAP protein was assessed by ELISA. Comparisons among Decitabine-treated, Cytarabine-treated, and untreated subgroups were analyzed using one-way ANOVA with Tukey's post hoc test.

Results: IL-1RAP mRNA increased in untreated CML (mean 4.01 ± 3.42 vs. control; P=0.001) and trended upward in Decitabine-treated AML (3.76 ± 1.76 vs. controls; P=0.1). IL-1RAP protein peaked in untreated AML (89.89 ± 53.53 ng/mL vs. controls 71.3 ± 24.9 ng/mL; P=0.01). CD26 mRNA were higher in untreated group (4.25 ± 1.3-fold change vs control; P = 0.001), followed by decitabine group 3.7 ± 0.81-fold change vs control; P = 0.01) and Cytarabine (364 ± 0.97-fold change vs control; P = 0.01) where in CML was (7.03 ± 4.20, P=0.0001).

Conclusions: IL-1RAP and CD26 exhibit therapy- and disease-specific regulation, with CD26 as a resilient biomarker. mRNA-protein discordance in IL-1RAP highlights post-therapeutic modulation. Combinatorial strategies (e.g., Decitabine with IL-1RAP inhibitors or CD26-targeted therapies) may overcome resistance, improving outcomes in high-risk AML/CML.

IL-1RAPCD26 (DPP4)CMLAML.Peipei C, Yasong DU. Research progress of interleukin-1 receptor accessory protein in the pathogenesis of neuropsychiatric diseases. Systems Engineering & Electronics. 2022;44(1).Frenay J, Bellaye PS, Oudot A, Helbling A, Petitot C, Ferrand C, et al. IL-1RAP, a Key Therapeutic Target in Cancer. Vol. 23, International Journal of Molecular Sciences. MDPI; 2022.Zhao K, Yuan S, Yin L, Xia J, Xu K. Potential Efficacy of Human IL-1RAP Specific CAR-T cell in Eliminating Leukemic Stem Cells of Chronic Myeloid Leukemia. Journal of Leukemia. 2017;05(02).Romzova M, Smitalova D, Taus P, Mayer J, Culen M. High Throughput Immunophenotyping and Expression Profiling at Single Cell Level Reveal BCR-ABL1 Dependent Surface Markers of Chronic Myeloid Leukemia Stem Cells. Blood. 2019 Nov 13;134(Supplement_1):2920–2920.Warda W, Larosa F, Neto Da Rocha M, Trad R, Deconinck E, Fajloun Z, et al. CML hematopoietic stem cells expressing IL1RAP can be targeted by chimeric antigen receptor–engineered T cells. Cancer Res. 2019;79(3):663–75.de Boer B, Sheveleva S, Apelt K, Vellenga E, Mulder AB, Huls G, et al. The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis. Haematologica. 2021 Dec 1;106(12):3067–78.Zhang Y, Park M, Ghoda LY, Zhao D, Valerio M, Nafie E, et al. IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells. J Hematol Oncol. 2024 Dec 1;17(1).Sheveleva S. Dissecting the Molecular Landscape of Acute Myeloid Leukemia [Internet]. University of Groningen; 2025. Available from: http://hdl.handle.net/11370/60c9e9a2-d0ad-4154-93a3-683eb1623828De Dreuzy E, Sayed SR El, Genin D, Primus C, Bouquet L, Collette A, et al. CCTx-001 CAR T-cells targeting the AML specific antigen IL-1RAP show robust pre-clinical anti-tumor efficacy. Cancer Res. 2024;84(6_Supplement):6322.Mitchell K, Barreyro L, Todorova TI, Taylor SJ, Antony-Debré I, Narayanagari SR, et al. IL1RAP potentiates multiple oncogenic signaling pathways in AML. Journal of Experimental Medicine. 2018 Jun 1;215(6):1709–27.Chitadze G, Wehkamp U, Janssen O, Brüggemann M, Lettau M. The serine protease CD26/DPP4 in non-transformed and malignant T cells. Vol. 13, Cancers. MDPI; 2021.Yan L, Tian X, Ye C, Guan X, Dong B, Zhao M, et al. CD26 as a promising biomarker for predicting prognosis in patients with pancreatic tumors. Onco Targets Ther. 2020;13:12615–23.Cordero OJ. CD26 and Cancer. Vol. 14, Cancers. MDPI; 2022.Camacho MF, Peña M, Toloza MJ, Moiraghi B, Enrico A, Mariano R, et al. Evaluation of leukemic stem cell (CD26 +) in chronic myeloid leukemia patients with different molecular responses and in treatment-free remission. Clin Exp Med [Internet]. 2025 Mar 21;25(1):93. Available from: https://link.springer.com/10.1007/s10238-025-01626-xZhou H, Jia B, Annageldiyev C, Minagawa K, Zhao C, Mineishi S, et al. CD26lowPD-1+ CD8 T cells are terminally exhausted and associated with leukemia progression in acute myeloid leukemia. Front Immunol. 2023;14.Busek P, Duke-Cohan JS, Sedo A. Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease? Vol. 14, Cancers. MDPI; 2022.Du F, Jin T, Wang L. Mechanism of Action of Decitabine in the Treatment of Acute Myeloid Leukemia by Regulating LINC00599. Analytical Cellular Pathology. 2023;2023.Roos Hilberink J. Decitabine in the treatment of acute myeloid leukemia: Clinical aspects and Immunological opportunities [Internet]. 2024. Available from: www.gildeprint.nlKim YJ, Li Z, Maiti A, Tanaka T, Uryu H, Furudate K, et al. Single-Cell Proteogenomics Analysis of AML Samples Treated with Decitabine and Venetoclax Reveals Divergent Treatment Escape Mechanisms. Blood. 2023;142:2931.Gu X, Tohme R, Tomlinson B, Hasipek M, Durkin L, Schuerger C, et al. Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network [Internet]. 2020. Available from: http://biorxiv.org/lookup/doi/10.1101/2020.02.20.958405Doval D, Kumar Sharma S, Kumar M, Khandelwal V, Choudhary D. Cytarabine ears – A side effect of cytarabine therapy. Journal of Oncology Pharmacy Practice. 2020 Mar 1;26(2):471–3.Hao Y, Ji M, Jin S, Li W, Zhou Y, Jia R, et al. Medium-cumulative dose of cytarabine in consolidation therapy shows the greatest benefit in AML patients. Holistic Integrative Oncology. 2024 May 21;3(1).Marrero RJ, Nicolet D, Shastri VM, Mrózek K, Walker CJ, Blum W, et al. Impact of Cytarabine Pharmacogenomics on Survival of Adolescent and Young Adults with AML and Its Clinical Relevance in Black Patients. Blood. 2023;142:2954.Sadeghi M, Moslehi A, Kheiry H, Kiani FK, Zarei A, Khodakarami A, et al. The sensitivity of acute myeloid leukemia cells to cytarabine is increased by suppressing the expression of Heme oxygenase-1 and hypoxia-inducible factor 1-alpha. Cancer Cell Int. 2024 Dec 1;24(1).Pereira-Vieira J, Weber DD, Silva S, Barbosa-Matos C, Granja S, Reis RM, et al. Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia. Pharmaceutics. 2024 Apr 1;16(4).Molica M, Breccia M, Foa R, Jabbour E, Kadia TM. Maintenance therapy in AML: The past, the present and the future. Vol. 94, American Journal of Hematology. Wiley-Liss Inc.; 2019. p. 1254–65.Zeki Aziz D, Homady MH, Kadim HA, Al-Kelaby KKA. ASSESSMENT OF COMPOUNDED DOXORUBICIN IN CARDIAC TISSUE OF EXPERIMENTAL ANIMALS. J Biotechnol [Internet]. 2017;14(4):811–6. Available from: www.pjbt.orgTrad R, Warda W, Alcazer V, Neto Da Rocha M, Berceanu A, Nicod C, et al. Chimeric antigen receptor T-cells targeting IL-1RAP: a promising new cellular immunotherapy to treat acute myeloid leukemia. J Immunother Cancer. 2022 Jul 1;10(7).Zhao K, Yin LL, Zhao DM, Pan B, Chen W, Cao J, et al. IL1RAP as a surface marker for leukemia stem cells is related to clinical phase of chronic myeloid leukemia patients [Internet]. Vol. 7, Int J Clin Exp Med. 2014. Available from: www.ijcem.com/Smitalová D, Culen M, Herudkova Z, Budinska E, Mayer J, Racil Z, et al. PF399 GENE EXPRESSION PROFILING OF CD26+ LEUKEMIC STEM CELL POPULATION FROM CML PATIENTS. Hemasphere. 2019 Jun;3(S1):151–2.