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

PRDM1, 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. PRDM1-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 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.

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Publication Details

Journal
Leukemia
Published
2025-12-09
DOI
https://doi.org/10.1038/s41375-025-02815-z
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.00
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article

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

Can Küçük, Sheng Pan, Wing C. Chan, Ru Chen et al.
Leukemia
Immune Cell Function and Interaction
article

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

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

Abstract

PRDM1, 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. PRDM1-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 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.

LeukemiaVol. 40(1)
Translational Genomics Research Institute (US), Beijing Tongren Hospital (CN), City Of Hope National Medical Center (US), Izmir University (TR), Baylor College of Medicine (US), Capital Medical University (CN), Dokuz Eylül University (TR), Peking University (CN), Beijing Tian Tan Hospital (CN), Peking University Cancer Hospital (CN), City of Hope (US), University of Nebraska Medical Center (US), The University of Texas Health Science Center at Houston (US)
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Immune Cell Function and Interaction
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