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SHR Neuro Cancer Cardio Lipid Metab Microb

Höckendorf, U; Dutta, S; Kloos, A; Runtsch, M; Zötsch, C; Vosberg, S; Wang, Y; Kienreich, S; Flasch, B; Malovan, G; Jäger, V; Stanzer, S; Prein, S; Odinius, TO; Wagner, CV; Buschhorn, L; Dill, V; Perfler, B; Haferlach, T; Döhner, K; Götze, KS; Ruland, J; Bassermann, F; Wahida, A; Heikenwälder, M; Branca, C; Schmöllerl, J; Zuber, J; Burk, AC; Zeiser, R; Sill, H; Jayavelu, AK; Zebisch, A; Heuser, M; Dengler, MA; Jost, PJ.
Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice.
Sci Transl Med. 2025; 17(826): eadu3313 Doi: 10.1126/scitranslmed.adu3313
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Leading authors Med Uni Graz

Dutta Sayantanee

Jost Philipp

Co-authors Med Uni Graz

Dengler Michael

Jäger Vanessa

Malovan Grazia

Perfler Bianca

Prein Stefanie

Runtsch Marah

Sill Heinz

Stanzer Stefanie

Vosberg Sebastian

Zebisch Armin

Zötsch Carina

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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 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.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Leukemia, Myeloid, Acute - drug therapy, pathology

Lymphotoxin-alpha - therapeutic use, pharmacology

Hematopoiesis - drug effects

Mice - administration & dosage

Humans - administration & dosage

Cell Differentiation - drug effects

Receptors, Tumor Necrosis Factor, Type I - metabolism

Neoplastic Stem Cells - drug effects, pathology, metabolism

Recombinant Proteins - pharmacology, therapeutic use

Receptors, Tumor Necrosis Factor, Type II - metabolism

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