Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis

• Published in: Cell death and differentiation Vol. 30; no. 6; pp. 1447 - 1456
• Main Authors: Potts, Margaret A., Mizutani, Shinsuke, Garnham, Alexandra L., Li Wai Suen, Connie S. N., Kueh, Andrew J., Tai, Lin, Pal, Martin, Strasser, Andreas, Herold, Marco J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2023; Nature Publishing Group
• Subjects: 13/1; 13/106; 38/91; 42/41; 631/250; 631/67; 64/60; Apoptosis; Biochemistry; Biomedical and Life Sciences; c-Myc protein; Cell Biology; Cell Cycle Analysis; Cell differentiation; CRISPR; Genomes; Life Sciences; Lymphocytes B; Lymphoma; Malignancy; Myc protein; Nucleotide sequence; Pax5 protein; Progenitor cells; Stem Cells; Transplantation
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-023-01145-w

Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered and their functions characterised, DNA sequence data of primary patient samples suggest that many more do exist. However, the nature of their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo [ 1 ]. CRISPR deletion of TFAP4 in Eµ-MYC transgenic haematopoietic stem and progenitor cells (HSPCs) and transplantation of these manipulated HSPCs into lethally irradiated animals significantly accelerated c-MYC-driven lymphoma development. Interestingly, TFAP4 deficient Eµ-MYC lymphomas all arose at the pre-B cell stage of B cell development. This observation prompted us to characterise the transcriptional profile of pre-B cells from pre-leukaemic mice transplanted with Eµ-MYC/Cas9 HSPCs that had been transduced with sgRNAs targeting TFAP4. This analysis revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1 , SpiB and Pax5 , which are direct target genes of both TFAP4 and MYC. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, thereby accelerating c-MYC-driven lymphoma development.