RESUMO
Myelodysplastic syndrome 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 an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvß-integrin/TGF-ß/SMAD pathway but, once established, was persistent because of 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 was directly regulated and induced by SMAD2/3 and, in turn, bound 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 an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-ß pathway or BATF.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Epigênese Genética , Células Matadoras Naturais , Leucemia Mieloide Aguda , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/imunologia , Humanos , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/imunologia , Animais , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais , Camundongos , Reprogramação Celular , Proteína Smad3/metabolismo , Proteína Smad2/metabolismoRESUMO
Since the advent of sequencing technologies in the 1990s, researchers have focused on the association between aberrations in chromosomal DNA and disease. However, not all forms of the DNA are linear and chromosomal. Extrachromosomal circular DNAs (eccDNAs) are double-stranded, closed-circled DNA constructs free from the chromosome that reside in the nuclei. Although widely overlooked, the eccDNAs have recently gained attention for their potential roles in physiological response, intratumoral heterogeneity and cancer therapeutics. In this review, we summarize the history, classifications, biogenesis, and highlight recent progresses on the emerging topic of eccDNAs and comment on their potential application as biomarkers in clinical settings.