1. IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.
- Author
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Rubino V, Hüppi M, Höpner S, Tortola L, Schnüriger N, Legenne H, Taylor L, Voggensperger S, Keller I, Bruggman R, Kronig MN, Bacher U, Kopf M, Ochsenbein AF, and Riether C
- Subjects
- Animals, Humans, Mice, Immunotherapy, Adoptive methods, Female, Mice, Inbred C57BL, Male, Receptors, Interleukin-21 metabolism, Receptors, Interleukin-21 genetics, Cell Differentiation drug effects, Xenograft Model Antitumor Assays, Cell Line, Tumor, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes drug effects, Interleukin-21, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute metabolism, Cytarabine pharmacology, Cytarabine therapeutic use, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Interleukins metabolism, Signal Transduction drug effects
- Abstract
Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4
+ T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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