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000306595 0247_ $$2ISSN$$a1946-6242
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000306595 1001_ $$00000-0002-8218-3343$$aHöckendorf, Ulrike$$b0
000306595 245__ $$aLymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice.
000306595 260__ $$aWashington, DC$$bAAAS$$c2025
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000306595 520__ $$aAcute 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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000306595 650_7 $$2NLM Chemicals$$aLymphotoxin-alpha
000306595 650_7 $$2NLM Chemicals$$aReceptors, Tumor Necrosis Factor, Type I
000306595 650_7 $$2NLM Chemicals$$aRecombinant Proteins
000306595 650_7 $$2NLM Chemicals$$aReceptors, Tumor Necrosis Factor, Type II
000306595 650_2 $$2MeSH$$aAnimals
000306595 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: drug therapy
000306595 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: pathology
000306595 650_2 $$2MeSH$$aLymphotoxin-alpha: therapeutic use
000306595 650_2 $$2MeSH$$aLymphotoxin-alpha: pharmacology
000306595 650_2 $$2MeSH$$aHematopoiesis: drug effects
000306595 650_2 $$2MeSH$$aMice
000306595 650_2 $$2MeSH$$aHumans
000306595 650_2 $$2MeSH$$aCell Differentiation: drug effects
000306595 650_2 $$2MeSH$$aReceptors, Tumor Necrosis Factor, Type I: metabolism
000306595 650_2 $$2MeSH$$aNeoplastic Stem Cells: drug effects
000306595 650_2 $$2MeSH$$aNeoplastic Stem Cells: pathology
000306595 650_2 $$2MeSH$$aNeoplastic Stem Cells: metabolism
000306595 650_2 $$2MeSH$$aRecombinant Proteins: pharmacology
000306595 650_2 $$2MeSH$$aRecombinant Proteins: therapeutic use
000306595 650_2 $$2MeSH$$aReceptors, Tumor Necrosis Factor, Type II: metabolism
000306595 7001_ $$aDutta, Sayantanee$$b1
000306595 7001_ $$00009-0001-4187-2513$$aKloos, Arnold$$b2
000306595 7001_ $$00000-0002-9059-9269$$aRuntsch, Marah$$b3
000306595 7001_ $$00000-0002-9228-210X$$aZötsch, Carina$$b4
000306595 7001_ $$aVosberg, Sebastian$$b5
000306595 7001_ $$0P:(DE-He78)54483eadd57bd53568e75b85a8711b96$$aWang, Yongjie$$b6$$udkfz
000306595 7001_ $$00009-0005-9871-6983$$aKienreich, Sophie$$b7
000306595 7001_ $$00009-0005-0271-6832$$aFlasch, Bettina$$b8
000306595 7001_ $$aMalovan, Grazia$$b9
000306595 7001_ $$00009-0003-7761-3606$$aJäger, Vanessa$$b10
000306595 7001_ $$00000-0002-5858-4067$$aStanzer, Stefanie$$b11
000306595 7001_ $$aPrein, Stefanie$$b12
000306595 7001_ $$00000-0002-9722-4582$$aOdinius, Timo O$$b13
000306595 7001_ $$aWagner, Celina V$$b14
000306595 7001_ $$00000-0001-7162-816X$$aBuschhorn, Lars$$b15
000306595 7001_ $$00000-0002-4258-4986$$aDill, Veronika$$b16
000306595 7001_ $$00009-0007-2302-301X$$aPerfler, Bianca$$b17
000306595 7001_ $$00000-0003-0196-2837$$aHaferlach, Torsten$$b18
000306595 7001_ $$aDöhner, Konstanze$$b19
000306595 7001_ $$00000-0002-6276-8002$$aGötze, Katharina S$$b20
000306595 7001_ $$00000-0002-8381-3597$$aRuland, Jürgen$$b21
000306595 7001_ $$00000-0003-4435-2609$$aBassermann, Florian$$b22
000306595 7001_ $$aWahida, Adam$$b23
000306595 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b24$$udkfz
000306595 7001_ $$aBranca, Caterina$$b25
000306595 7001_ $$00000-0002-8461-8881$$aSchmöllerl, Johannes$$b26
000306595 7001_ $$00000-0001-8810-6835$$aZuber, Johannes$$b27
000306595 7001_ $$aBurk, Ann-Cathrin$$b28
000306595 7001_ $$00000-0001-6565-3393$$aZeiser, Robert$$b29
000306595 7001_ $$00000-0003-0993-4371$$aSill, Heinz$$b30
000306595 7001_ $$0P:(DE-He78)1546aa03aab6491ab3cf01f75ac2b6af$$aJayavelu, Ashok Kumar$$b31$$udkfz
000306595 7001_ $$00000-0002-4861-7021$$aZebisch, Armin$$b32
000306595 7001_ $$aHeuser, Michael$$b33
000306595 7001_ $$00000-0002-1693-1761$$aDengler, Michael A$$b34
000306595 7001_ $$00000-0003-2454-0362$$aJost, Philipp J$$b35
000306595 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.adu3313$$gVol. 17, no. 826, p. eadu3313$$n826$$peadu3313$$tScience translational medicine$$v17$$x1946-6234$$y2025
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