TY  - JOUR
AU  - Höckendorf, Ulrike
AU  - Dutta, Sayantanee
AU  - Kloos, Arnold
AU  - Runtsch, Marah
AU  - Zötsch, Carina
AU  - Vosberg, Sebastian
AU  - Wang, Yongjie
AU  - Kienreich, Sophie
AU  - Flasch, Bettina
AU  - Malovan, Grazia
AU  - Jäger, Vanessa
AU  - Stanzer, Stefanie
AU  - Prein, Stefanie
AU  - Odinius, Timo O
AU  - Wagner, Celina V
AU  - Buschhorn, Lars
AU  - Dill, Veronika
AU  - Perfler, Bianca
AU  - Haferlach, Torsten
AU  - Döhner, Konstanze
AU  - Götze, Katharina S
AU  - Ruland, Jürgen
AU  - Bassermann, Florian
AU  - Wahida, Adam
AU  - Heikenwälder, Mathias
AU  - Branca, Caterina
AU  - Schmöllerl, Johannes
AU  - Zuber, Johannes
AU  - Burk, Ann-Cathrin
AU  - Zeiser, Robert
AU  - Sill, Heinz
AU  - Jayavelu, Ashok Kumar
AU  - Zebisch, Armin
AU  - Heuser, Michael
AU  - Dengler, Michael A
AU  - Jost, Philipp J
TI  - Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice.
JO  - Science translational medicine
VL  - 17
IS  - 826
SN  - 1946-6234
CY  - Washington, DC
PB  - AAAS
M1  - DKFZ-2025-02634
SP  - eadu3313
PY  - 2025
AB  - 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 lymphotoxin alpha (Lta) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα3) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα3 resulted in deep and durable remissions. LTα3 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, LTα3 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.
KW  - Animals
KW  - Leukemia, Myeloid, Acute: drug therapy
KW  - Leukemia, Myeloid, Acute: pathology
KW  - Lymphotoxin-alpha: therapeutic use
KW  - Lymphotoxin-alpha: pharmacology
KW  - Hematopoiesis: drug effects
KW  - Mice
KW  - Humans
KW  - Cell Differentiation: drug effects
KW  - Receptors, Tumor Necrosis Factor, Type I: metabolism
KW  - Neoplastic Stem Cells: drug effects
KW  - Neoplastic Stem Cells: pathology
KW  - Neoplastic Stem Cells: metabolism
KW  - Recombinant Proteins: pharmacology
KW  - Recombinant Proteins: therapeutic use
KW  - Receptors, Tumor Necrosis Factor, Type II: metabolism
KW  - Lymphotoxin-alpha (NLM Chemicals)
KW  - Receptors, Tumor Necrosis Factor, Type I (NLM Chemicals)
KW  - Recombinant Proteins (NLM Chemicals)
KW  - Receptors, Tumor Necrosis Factor, Type II (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41296826
DO  - DOI:10.1126/scitranslmed.adu3313
UR  - https://inrepo02.dkfz.de/record/306595
ER  -