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SHR Neuro Krebs Kardio Lipid Stoffw 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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Autor*innen der Med Uni Graz:
Dengler Michael
Dutta Sayantanee
Jäger Vanessa
Jost Philipp
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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