Journal Article

DKFZ-2025-02634

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice.

Höckendorf, U. ; Dutta, S. ; Kloos, A. ; Runtsch, M. ; Zötsch, C. ; Vosberg, S. ; Wang, Y.DKFZ* ; 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.DKFZ* ; Ruland, J.DKFZ* ; Bassermann, F.DKFZ* ; Wahida, A. ; Heikenwälder, M.DKFZ* ; Branca, C. ; Schmöllerl, J. ; Zuber, J. ; Burk, A.-C. ; Zeiser, R. ; Sill, H. ; Jayavelu, A. K.DKFZ* ; Zebisch, A. ; Heuser, M. ; Dengler, M. A. ; Jost, P. J.

2025
AAAS Washington, DC

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.

Keyword(s): Animals (MeSH) ; Leukemia, Myeloid, Acute: drug therapy (MeSH) ; Leukemia, Myeloid, Acute: pathology (MeSH) ; Lymphotoxin-alpha: therapeutic use (MeSH) ; Lymphotoxin-alpha: pharmacology (MeSH) ; Hematopoiesis: drug effects (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Cell Differentiation: drug effects (MeSH) ; Receptors, Tumor Necrosis Factor, Type I: metabolism (MeSH) ; Neoplastic Stem Cells: drug effects (MeSH) ; Neoplastic Stem Cells: pathology (MeSH) ; Neoplastic Stem Cells: metabolism (MeSH) ; Recombinant Proteins: pharmacology (MeSH) ; Recombinant Proteins: therapeutic use (MeSH) ; Receptors, Tumor Necrosis Factor, Type II: metabolism (MeSH) ; Lymphotoxin-alpha ; Receptors, Tumor Necrosis Factor, Type I ; Recombinant Proteins ; Receptors, Tumor Necrosis Factor, Type II

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Contributing Institute(s):

1. KKE Pädiatrische Leukämie (A400)
2. DKTK Koordinierungsstelle München (MU01)
3. Chronische Entzündung und Krebs (D440)

Research Program(s):

1. 319H - Addenda (POF4-319H) (POF4-319H)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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