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@ARTICLE{Hckendorf:306595,
author = {U. Höckendorf and S. Dutta and A. Kloos and M. Runtsch and
C. Zötsch and S. Vosberg and Y. Wang$^*$ and S. Kienreich
and B. Flasch and G. Malovan and V. Jäger and S. Stanzer
and S. Prein and T. O. Odinius and C. V. Wagner and L.
Buschhorn and V. Dill and B. Perfler and T. Haferlach and K.
Döhner and K. S. Götze$^*$ and J. Ruland$^*$ and F.
Bassermann$^*$ and A. Wahida and M. Heikenwälder$^*$ and C.
Branca and J. Schmöllerl and J. Zuber and A.-C. Burk and R.
Zeiser and H. Sill and A. K. Jayavelu$^*$ and A. Zebisch and
M. Heuser and M. A. Dengler and P. J. Jost},
title = {{L}ymphotoxin alpha eradicates acute myeloid leukemia and
simultaneously promotes healthy hematopoiesis in mice.},
journal = {Science translational medicine},
volume = {17},
number = {826},
issn = {1946-6234},
address = {Washington, DC},
publisher = {AAAS},
reportid = {DKFZ-2025-02634},
pages = {eadu3313},
year = {2025},
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.},
keywords = {Animals / Leukemia, Myeloid, Acute: drug therapy /
Leukemia, Myeloid, Acute: pathology / Lymphotoxin-alpha:
therapeutic use / Lymphotoxin-alpha: pharmacology /
Hematopoiesis: drug effects / Mice / Humans / Cell
Differentiation: drug effects / Receptors, Tumor Necrosis
Factor, Type I: metabolism / Neoplastic Stem Cells: drug
effects / Neoplastic Stem Cells: pathology / Neoplastic Stem
Cells: metabolism / Recombinant Proteins: pharmacology /
Recombinant Proteins: therapeutic use / Receptors, Tumor
Necrosis Factor, Type II: metabolism / Lymphotoxin-alpha
(NLM Chemicals) / Receptors, Tumor Necrosis Factor, Type I
(NLM Chemicals) / Recombinant Proteins (NLM Chemicals) /
Receptors, Tumor Necrosis Factor, Type II (NLM Chemicals)},
cin = {A400 / MU01 / D440},
ddc = {500},
cid = {I:(DE-He78)A400-20160331 / I:(DE-He78)MU01-20160331 /
I:(DE-He78)D440-20160331},
pnm = {319H - Addenda (POF4-319H)},
pid = {G:(DE-HGF)POF4-319H},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41296826},
doi = {10.1126/scitranslmed.adu3313},
url = {https://inrepo02.dkfz.de/record/306595},
}