The transcriptional regulator PRDM1: Key insights into its role in NK cell homeostasis and malignancy

Natural killer cell lymphoma (NKCL) is an aggressive type of cancer with poor prognosis. As a rare cancer type with geographic predilection, it was of utmost significance to identify the cancer- associated genes contributing to development of NKCL. Our previous study revealed recurrent deletions of 6q21 locus that includes PRDM1 among other candidate tumor suppressor genes. As a transcriptional repressor, the role of PRDM1 was well characterized in normal as well as neoplastic B and T cells but there was little insight on its role in NK cell pathobiology. Importantly, we observed truncating mutations and/or promoter hypermethylation in malignant NK cell lines, which was associated with its underexpression. Further analyses with primary NKCL tumor samples revealed frequent inactivation of PRDM1 through a cooperation of mono-allelic deletion and promoter-associated hypermethylation. Functional experiments with malignant NK cell lines and primary NK cells revealed that PRDM1 acts as a tumor suppressor by inducing cell cycle arrest and apoptosis. The strong negative selection pressure observed in NK cell lines with ectopic PRDM1 expression was stronger when IL-2 concentration is limiting. Consistent with this observation, we showed that PRDM1 decreases sensitivity of human NK cells to IL2-induced cell proliferation by directly repressing CD25 (IL2RA). Our recent analyses of the transcriptional targets of PRDM1 in NK cell lines showed downregulation of several important genes associated with NK cell activation including but not limited to those involved in proliferation, survival, or antiviral defense. In conclusion, our observations altogether suggest a key regulatory role of PRDM1 in human NK cells that contribute to NKCL pathogenesis when it loses its function through genetic and/or epigenetic aberrations. Re-expression of PRDM1 may be an effective therapeutic strategy for treatment of these aggressive malignancies.

Assoc. Prof. Dr. Can Küçük completed his Ph.D. studies on oncology and cancer biology at the University of Nebraska Medical Center (UNMC). He performed post-doctoral studies at UNMC and City of Hope Medical Center. Dr. Küçük has publications in high impact journals such as Nature Communications, Blood, or PNAS. He earned prestigious international awards from the American Society of Hematology and the National Natural Science Foundation of China. Dr. Küçük’s research focuses on genomic, transcriptomic, and epigenomic aberrations causing lymphoid cancers to identify biomarkers that can improve diagnosis or prognostication of lymphoid cancers and to discover more effective therapeutic targets.