Abstract Frequent relapse driven by resistant leukemic stem or progenitor cells (LSC) represents one of the major challenges in acute myeloid leukemia (AML) therapy. Based on the concept of cytokine-induced myeloid differentiation as observed during emergency granulopoiesis of healthy hematopoeitic progenitors, we dissected individual cytokines for their effect on myeloid differentiation of LSCs.We identified that cytokines from the TNF family potently induced cellular differentiation in LSCs from a range of different genetic backgrounds of AML. The induction of this differentiation program is driven, at least in part, by the activation of programmed inflammatory cell death and subsequent release of pro-inflammatory cytokines such as IL-1beta. Mechanistically, we identified that TNFR receptor 1 (TNFR1)-mediated signaling induces Receptor-interacting protein kinase 3 (RIPK3) dependent cell death of LSCs upon loss of the pro-survival protein TNFR associated factor 2 (TRAF2). TNF family cytokines such as Lymphotoxin alpha (LTα3) efficiently repress leukemia by depleting TRAF2 from the intracellular pool of LSCs via activation of both TNFR1 and TNFR2. Competitive and simultaneous recruitment of TRAF2 to both TNFR1 and TNFR2 results in the failure of LSCs to generate a robust pro-survival signaling complex I at the proximal portion of TNFR1. This results in RIPK3-dependent inflammatory cell death of LSCs.Of note, in contrast to conventional therapies, LTα3 exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. This cytokine-induced propagation of healthy progenitor cells mimics the process observed during emergency granulopoiesis. Exposure of healthy primary human bone marrow progenitors to LTα3 resulted in propagation of healthy progenitors cells. Co-treatment of malignant and healthy progenitor cells from AML patients within the same culture repressed the malignant LSCs but propagated the healthy progenitors. Accordingly, this tumor-suppressive mechanism can be harnessed to simultaneously clear malignant progenitors cells and promote healthy hematopoiesis.In mouse model systems, genetic deletion of the TNF superfamily member gene lymphotoxin alpha (Lta) blocked cell death and accelerated leukemogenesis. In patient-derived xenograft mouse models, exposure to recombinant LTα3 resulted in deep and sustained remissions. Leveraging this endogenous tumor-suppressive mechanism may de-couple treatment efficacy on malignant cells from undesired bone marrow (BM) suppression. Citation Format: Philipp J. Jost, Ulrike Höckendorf, Sayantanee Dutta, Arnold Kloos, Marah Runtsch, Carina Zötsch, Sebastian Vosberg, Yongjie Wang, Sophie Kienreich, Bettina Flasch, Grazia Malovan, Vanessa Jäger, Stefanie Stanzer, Stefanie Preis, Timo O. Odinius, Celina V. Wagner, Lars Buschhorn, Veronika Dill, Bianca Perfler, Torsten Haferlach, Konstanze Döhner, Katharina S. Götze, Jürgen Ruland, Florian Bassermann, Adam Wahida, Mathias Heikenwälder, Caterina Branca, Johannes Schmöllerl, Johannes Zuber, Ann-Cathrin Burk, Robert Zeiser, Heinz Sill, Ashok Kumar Jayavelu, Armin Zebisch, Michael Heuser, Michael A. Dengler. Lymphotoxin alpha induces myeloid differentiation and programmed cell death in myeloid leukemic stem cells resulting in deep and sustained remission in vivo abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3984.
Jost et al. (Fri,) studied this question.