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<p><i>PRDM1</i>, encoding a transcription factor (TF), regulates plasma cell and CD8<sup>+</sup> T-cell terminal differentiation and T<sub>h</sub>2 lineage specification, while its role in human NK-cell differentiation and homeostasis is largely unknown. Here, we employed a multi-omics approach to dissect the transcriptional control of PRDM1 on human NK-cells. PRDM1 is important in NK-cell terminal differentiation based on gene expression profiling and its targeting of key regulators in the process. <i>PRDM1</i>-deleted NK-cells displayed a less mature phenotype simulating the CD56<sup>bright</sup> NK-cell population accompanied by upregulation of stem-like gene signatures. PRDM1-bound genes were enriched in T/NK-cell receptor signaling, activation, and NK-cell effector functions. PRDM1 could function as a transcriptional repressor as well as an activator as its activities may be modified by association with different TFs and co-factors. The kinetics of its action also varies among its target genes. As a homeostatic factor, PRDM1 is induced upon IL-2 and feeder cell stimulation, but its ability to restrict NK-cell growth upon feeder stimulation may be counteracted by the AP-1-induced transcriptional network. The loss of <i>PRDM1</i> activity is frequent in NK-cell malignancies which may lead to decreased homeostatic control, impaired terminal differentiation, enhanced cellular fitness, and the acquisition of more stem-like features, thereby promoting lymphomagenesis.</p>

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Key regulatory roles of PRDM1 in human NK-cell differentiation and activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • Xuxiang Liu,
  • Yunfei Shi,
  • Jibin Zhang,
  • Kunal Shetty,
  • Krystie Chew,
  • Can Küçük,
  • Qiang Gong,
  • Esra Esmeray,
  • Haiqing Li,
  • Ru Chen,
  • Sheng Pan,
  • Katarzyna Dąbrowska,
  • Roger E. Moore,
  • Krystine Garcia-Mansfield,
  • Patrick Pirrotte,
  • Jinhui Wang,
  • Yuping Li,
  • Gehong Dong,
  • Logan Lee,
  • Timothy W. McKeithan,
  • Javeed Iqbal,
  • Wing C. Chan

摘要

PRDM1, encoding a transcription factor (TF), regulates plasma cell and CD8+ T-cell terminal differentiation and Th2 lineage specification, while its role in human NK-cell differentiation and homeostasis is largely unknown. Here, we employed a multi-omics approach to dissect the transcriptional control of PRDM1 on human NK-cells. PRDM1 is important in NK-cell terminal differentiation based on gene expression profiling and its targeting of key regulators in the process. PRDM1-deleted NK-cells displayed a less mature phenotype simulating the CD56bright NK-cell population accompanied by upregulation of stem-like gene signatures. PRDM1-bound genes were enriched in T/NK-cell receptor signaling, activation, and NK-cell effector functions. PRDM1 could function as a transcriptional repressor as well as an activator as its activities may be modified by association with different TFs and co-factors. The kinetics of its action also varies among its target genes. As a homeostatic factor, PRDM1 is induced upon IL-2 and feeder cell stimulation, but its ability to restrict NK-cell growth upon feeder stimulation may be counteracted by the AP-1-induced transcriptional network. The loss of PRDM1 activity is frequent in NK-cell malignancies which may lead to decreased homeostatic control, impaired terminal differentiation, enhanced cellular fitness, and the acquisition of more stem-like features, thereby promoting lymphomagenesis.