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

Abstract

Abstract PRDM1 , encoding a transcription factor (TF), regulates plasma cell and CD8 + T-cell terminal differentiation and T h 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. PRDM1 -deleted NK-cells displayed a less mature phenotype simulating the CD56 bright 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.

Affiliated Institutions

• City of Hope US
• Beijing Tian Tan Hospital CN
• Dokuz Eylül University TR
• Translational Genomics Research Institute US
• The University of Texas Health Science Center at Houston US
• Capital Medical University CN
• City Of Hope National Medical Center US
• Izmir University TR
• Baylor College of Medicine US
• Beijing Tongren Hospital CN

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