Key Regulatory Roles of PRDM1 in Human Nk-Cell Differentiation and Activation

Authors

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

Language

English

Publication Date

1-1-2026

Journal

Leukemia

DOI

10.1038/s41375-025-02815-z

PMID

41366532

PMCID

PMC12789010

PubMedCentral® Posted Date

12-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Positive Regulatory Domain I-Binding Factor 1, Killer Cells, Natural, Cell Differentiation, Lymphocyte Activation, Gene Expression Regulation, Gene Expression Profiling, Non-hodgkin lymphoma, Lymphocytes, Oncogenes

Published Open-Access

yes

Recommended Citation

Liu, Xuxiang; Shi, Yunfei; Zhang, Jibin; et al., "Key Regulatory Roles of PRDM1 in Human Nk-Cell Differentiation and Activation" (2026). Faculty, Staff and Student Publications. 6389.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6389