Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice

Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the tumor necrosis factor (TNF) superfamily member <i>lymphotoxin alpha</i> (<i>Lta</i>) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα<sub>3</sub>) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα<sub>3</sub> resulted in deep and durable remissions. LTα<sub>3</sub> repressed leukemia by depleting tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) through activation of TNF receptors TNFR1 and TNFR2. In contrast with conventional therapies, LTα<sub>3</sub> exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. Leveraging this endogenous tumor-suppressive mechanism may decouple treatment efficacy on malignant cells from undesired bone marrow suppression.

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Publication Details

Journal
Science Translational Medicine
Published
2025-11-26
DOI
https://doi.org/10.1126/scitranslmed.adu3313
Primary Topic
Immune Response and Inflammation
Type
article
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article

Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice

Celina V. Wagner, Bianca Perfler, Ann‐Cathrin Burk, Sayantanee Dutta et al.
Science Translational Medicine
Immune Response and Inflammation
article

Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice

Celina V. Wagner, Bianca Perfler, Ann‐Cathrin Burk, Sayantanee Dutta, Caterina Branca, Lars Buschhorn, Veronika Dill, Mathias Heikenwälder, Johannes Schmoellerl, Vanessa Jäger, Timo O. Odinius, Armin Zebisch, Ashok Kumar Jayavelu, Ulrike Höckendorf, Torsten Haferlach, Sebastian Vosberg, Michael Heuser, Konstanze Döhner, Florian C. Bassermann, Marah C. Runtsch, Sophie Kienreich, Katharina S. S. Götze, Jürgen Ruland, Heinz Sill, Stefanie Stanzer, Adam Wahida, Robert Zeiser, Michael A. Dengler, Philipp J. Jost, Johannes Zuber, Yongjie Wang, Arnold Kloos, Stefanie Prein, Bettina Flasch, Grazia Malovan, Carina Zötsch
article en

Abstract

Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the tumor necrosis factor (TNF) superfamily member <i>lymphotoxin alpha</i> (<i>Lta</i>) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα<sub>3</sub>) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα<sub>3</sub> resulted in deep and durable remissions. LTα<sub>3</sub> repressed leukemia by depleting tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) through activation of TNF receptors TNFR1 and TNFR2. In contrast with conventional therapies, LTα<sub>3</sub> exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. Leveraging this endogenous tumor-suppressive mechanism may decouple treatment efficacy on malignant cells from undesired bone marrow suppression.

Science Translational MedicineVol. 17(826)
German Cancer Research Center (DE), Research Institute of Molecular Pathology (AT), Medical University of Graz (AT), Heidelberg University (DE), University Medical Center Freiburg (DE), University Hospital Heidelberg (DE), TUM Klinikum (DE), Helmholtz Zentrum München (DE), Medizinische Hochschule Hannover (DE), Munich Leukemia Laboratory (Germany) (DE), University Hospital of Zurich (CH), Private Pädagogische Hochschule Augustinum (AT), Translational Research in Oncology (FR), National Center for Tumor Diseases (DE), BioTechMed-Graz (AT), Hopp Children's Cancer Center Heidelberg (DE), Vienna Biocenter (AT), University Hospital Ulm (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Technical University of Munich (DE), Martin Luther University Halle-Wittenberg (DE), Medical University of Vienna (AT)
Openalex Percentile: Top 59%
Immune Response and Inflammation
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