Impact of Bone Marrow miR-21 Expression on Acute Myeloid Leukemia T Lymphocyte Fragility and Dysfunction
Douâa Moussa Agha,
Redouane Rouas,
Mehdi Najar,
Fatima Bouhtit,
Hussein Fayyad-Kazan,
Laurence Lagneaux,
Dominique Bron,
Nathalie Meuleman,
Philippe Lewalle,
Makram Merimi
Affiliations
Douâa Moussa Agha
Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Bruxelles, Belgium
Redouane Rouas
Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Bruxelles, Belgium
Mehdi Najar
Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM) and Department of Medicine, University of Montreal, Montreal, QC H2X 0A9, Canada
Fatima Bouhtit
Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Bruxelles, Belgium
Hussein Fayyad-Kazan
Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath 90656, Lebanon
Laurence Lagneaux
Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles, 1070 Bruxelles, Belgium
Dominique Bron
Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Bruxelles, Belgium
Nathalie Meuleman
Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Bruxelles, Belgium
Philippe Lewalle
Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Bruxelles, Belgium
Makram Merimi
Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Bruxelles, Belgium
Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy in which antitumor immunity is impaired. The therapeutic management of AML requires understanding the mechanisms involved in the fragility and immune dysfunction of AML T lymphocytes. Methods: In this study, T lymphocytes from healthy donors (HD) and AML patients were used. Extracellular vesicles (EVs) from leukemic cells were screened for their microRNA content and impact on T lymphocytes. Flow cytometry, transcriptomic as well as lentiviral transduction techniques were used to carry out the research. Results: We observed increased cell death of T lymphocytes from AML patients. EVs from leukemia myeloid cell lines harbored several miRNAs, including miR-21, and were able to induce T lymphocyte death. Compared to that in HD, miR-21 was overexpressed in both the bone marrow fluid and infiltrating T lymphocytes of AML patients. MiR-21 induces T lymphocyte cell death by upregulating proapoptotic gene expression. It also increases the immunosuppressive profile of T lymphocytes by upregulating the IL13, IL4, IL10, and FoxP3 genes. Conclusions: Our results demonstrate that miR-21 plays a significant role in AML T lymphocyte dysfunction and apoptosis. Targeting miR-21 may be a novel approach to restore the efficacy of the immune response against AML.
