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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, T.O.* ; Wagner, C.V.* ; Buschhorn, L.* ; Dill, V.* ; Perfler, B.* ; Haferlach, T.* ; Döhner, K.* ; Götze, K.S.* ; Ruland, J.* ; Bassermann, F.* ; Wahida, A. ; Heikenwälder, M.* ; Branca, C.* ; Schmöllerl, J.* ; Zuber, J.* ; Burk, A.C.* ; Zeiser, R.* ; Sill, H.* ; Jayavelu, A.K.* ; Zebisch, A.* ; Heuser, M.* ; Dengler, M.A.* ; Jost, P.J.*

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

Sci. Transl. Med. 17:eadu3313 (2025)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Tumor-necrosis-factor; Stem-cells; Progenitor Cells; Tnf-alpha; Pathogen Signals; Knockout Mice; Identification; Deficient; Receptors; Immune
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Zeitschrift Science Translational Medicine
Quellenangaben Band: 17, Heft: 826, Seiten: , Artikelnummer: eadu3313 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Förderungen
DFG from the Else-Kroner-Fresenius Stiftung
ERC CoG BCM-UPS
DFG
Deutsche Krebshilfe
DJCLS
ERC grant under the European Union
EOS grant (Netherlands)
ERC CoG HepatometaboPath
German Cancer Aid
Mildred Scheel PhD program
RU5659TARGET-MPN: HE6233/15-1 Multilateral Initiatives
FWF
EU HORIZON-WIDERA-2023-ACCESS-02
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB 1335
European Research Council (ERC) under the European Union
Biobank Graz
Austrian Research Promotion Agency
Fellinger Cancer Research Foundation
Austrian Science Fund
Austrian Academy of Sciences
Boehringer Ingelheim
Mirimus Inc.
European Union: EU
Gottfried Wilhelm Leibniz program (DFG)
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-SFB-1479
Leukemia & Lymphoma Society
DFG Emmy Noether
ERA-NETTRANSCAN-3 initiative (Austrian Science Funds)
Leukamiehilfe Steiermarkto H.S. Austrian Science Fund (FWF)