Induction of Mitochondrial Apoptosis and Suppression of Autophagic Pathways in T-Cell Acute Lymphoblastic Leukemia Cells by Natural Killer Cell–Derived Exosomes
4 affiliations
- 1Associate Professor, Ph.D. in Medical Immunology, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2Ph.D. in Pharmaceutical Biotechnology, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 3MD, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 4Assistant Professor, Ph.D. in Medical Immunology, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Abstract
Introduction: Acute lymphoblastic leukemia (ALL) is one of the most common hematologic malignancies, in which treatment resistance and disease relapse remain major clinical challenges. Natural killer (NK) cells release exosomes containing cytotoxic molecules that can exert anti-tumor effects without requiring direct cell-to-cell contact. Considering the critical role of the apoptosis–autophagy balance in leukemic cell survival, the present study aimed to investigate the effect of NK cell–derived exosomes on this regulatory axis in the MOLT-4 cell line. Methods: In this experimental study, NK cells were isolated from the peripheral blood of healthy donors using magnetic-activated cell sorting (MACS) and activated with IL-2. Exosomes were extracted from culture supernatants and characterized in terms of morphology and size. MOLT-4 cells were then treated with NK-derived exosomes for 48 h. Apoptosis was assessed by flow cytometry using Annexin V/PI staining. The expression levels of BAX, BCL2, Caspase-9 (CASP9), Beclin-1 (BECN1), ATG5, LC3B, and FOXO1 were evaluated by quantitative real-time PCR. Results: Treatment with NK cell–derived exosomes significantly increased the percentage of apoptotic cells (P < 0.001). Expression levels of BAX (P < 0.0005) and CASP9 (P < 0.0014) were significantly upregulated, while BCL2 expression (P < 0.05) was downregulated, resulting in an increased BAX/BCL2 ratio. Concurrently, the expression of autophagy-related genes, including BECN1 (P < 0.013), ATG5 (P < 0.009), and LC3B (P < 0.037), as well as the transcription factor FOXO1 (P < 0.01), was significantly decreased. Conclusion: NK cell–derived exosomes reduce the survival of acute lymphoblastic leukemia cells by inducing intrinsic apoptotic pathways and suppressing autophagic signaling. These findings suggest that NK-derived exosomes may represent a novel strategy in extracellular vesicle–based immunotherapy.
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BibTeX
@article{aghebatimaleki2026induction,
title = {{Induction of Mitochondrial Apoptosis and Suppression of Autophagic Pathways in T-Cell Acute Lymphoblastic Leukemia Cells by Natural Killer Cell–Derived Exosomes}},
author = {Leili Aghebati-Maleki and Vida Ebrahimi and Siamak Sandoghchian Shotorbani and Ghasem Aghazadeh Balkanlou and Mohammad Sadegh Soltani-Zangbar},
journal = {مجله دانشگاه علوم پزشکی خراسان شمالی},
year = {2026},
month = sep,
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Induction of Mitochondrial Apoptosis and Suppression of Autophagic Pathways in T-Cell Acute Lymphoblastic Leukemia Cells by Natural Killer Cell–Derived Exosomes
AU - Leili Aghebati-Maleki
AU - Vida Ebrahimi
AU - Siamak Sandoghchian Shotorbani
AU - Ghasem Aghazadeh Balkanlou
AU - Mohammad Sadegh Soltani-Zangbar
PY - 2026
DA - 2026/09/01
JO - مجله دانشگاه علوم پزشکی خراسان شمالی
AB - Introduction: Acute lymphoblastic leukemia (ALL) is one of the most common hematologic malignancies, in which treatment resistance and disease relapse remain major clinical challenges. Natural killer (NK) cells release exosomes containing cytotoxic molecules that can exert anti-tumor effects without requiring direct cell-to-cell contact. Considering the critical role of the apoptosis–autophagy balance in leukemic cell survival, the present study aimed to investigate the effect of NK cell–derived exosomes on this regulatory axis in the MOLT-4 cell line. Methods: In this experimental study, NK cells were isolated from the peripheral blood of healthy donors using magnetic-activated cell sorting (MACS) and activated with IL-2. Exosomes were extracted from culture supernatants and characterized in terms of morphology and size. MOLT-4 cells were then treated with NK-derived exosomes for 48 h. Apoptosis was assessed by flow cytometry using Annexin V/PI staining. The expression levels of BAX, BCL2, Caspase-9 (CASP9), Beclin-1 (BECN1), ATG5, LC3B, and FOXO1 were evaluated by quantitative real-time PCR. Results: Treatment with NK cell–derived exosomes significantly increased the percentage of apoptotic cells (P < 0.001). Expression levels of BAX (P < 0.0005) and CASP9 (P < 0.0014) were significantly upregulated, while BCL2 expression (P < 0.05) was downregulated, resulting in an increased BAX/BCL2 ratio. Concurrently, the expression of autophagy-related genes, including BECN1 (P < 0.013), ATG5 (P < 0.009), and LC3B (P < 0.037), as well as the transcription factor FOXO1 (P < 0.01), was significantly decreased. Conclusion: NK cell–derived exosomes reduce the survival of acute lymphoblastic leukemia cells by inducing intrinsic apoptotic pathways and suppressing autophagic signaling. These findings suggest that NK-derived exosomes may represent a novel strategy in extracellular vesicle–based immunotherapy.
SN - 2008-8701
SN - 2008-8698
ER -