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Lymphotoxin alpha is an endogenous repressor of acute myeloid leukemia

ABSTRACT: Acute myeloid (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem cells (LSC)1, highlighting the necessity to target the malignant stem-cell pool for disease control. Here, we report a tumor suppressive mechanism that can be harnessed to clear LSC while promoting healthy hematopoiesis. We discovered that genetic deletion of homotrimeric lymphotoxin alpha (LTα3) blocks cell death and accelerates leukemogenesis in a murine model of FLT3-ITD+ AML. Accordingly, exposure of primary murine or human AML cells to exogenous recombinant LTα3 stimulates cell death and myeloid differentiation. In leukemia-bearing mice and AML patient-derived xenografts, recombinant LTα3 induces deep and lasting remissions even in PDX samples with adverse genetic profiles. Mechanistically, LTα3 represses leukemia by depleting TNFR-associated factor 2 (TRAF2) via TNF receptor (TNFR)1 and TNFR2. In contrast to most AML therapies, LTα3 exerts little to no toxicity on healthy hematopoiesis but rather boosts healthy hematopoietic progenitor cells thereby effectively uncoupling leukemia treatment from unwanted BM suppression. Leveraging this endogenous TRAF2-dependent negative feedback loop in leukemia, our data suggest that recombinant LTα3 represents a therapeutic opportunity for AML eradication.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270116 | GEO | 2025/11/26

REPOSITORIES: GEO

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miR-126 Governs Human Leukemia Stem Cell Quiescence and Therapeutic Resistance

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2016-03-31 | PXD001994 | Pride

miR-126 governs human leukemia stem cell quiescence and therapeutic resistance

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