Faculty, Staff and Student Publications

Language

English

Publication Date

9-11-2024

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.adp0004

PMID

39259809

PMCID

PMC11967735

PubMedCentral® Posted Date

9-11-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism and exhausted phenotype at the single cell transcriptomic and proteomic levels. In this study we identified that this dysfunction was mediated through a crosstalk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ integrin/TGF-β/SMAD pathway but, once established, was persistent due to profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF is directly regulated and induced by SMAD2/3 and in turn binds to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.

Keywords

Leukemia, Myeloid, Acute, Humans, Epigenesis, Genetic, Basic-Leucine Zipper Transcription Factors, Killer Cells, Natural, Animals, Transforming Growth Factor beta, Signal Transduction, Mice, Cellular Reprogramming, Smad3 Protein, Smad2 Protein

Published Open-Access

yes

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