Effects of ikaros (IKZF1) gene in the virulence of marek's disease virus

Authors: Kim, Taejoong; NIIKURA, MASAHIRO - Simon Frasier University; Dunn, John; Cheng, Hans; Hearn, Cari

Submitted to: Veterinary Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2025
Publication Date: 4/28/2025
Citation: Kim, T.N., Niikura, M., Dunn, J.R., Cheng, H.H., Hearn, C.J. 2025. Effects of Ikaros (IKZF1) gene in the virulence of Marek's disease virus. Veterinary Microbiology. 305(110532). https://doi.org/10.1016/j.vetmic.2025.110532.
DOI: https://doi.org/10.1016/j.vetmic.2025.110532

Interpretive Summary: Marek's Disease (MD), a disease caused by the avian herpesvirus Marek's Disease Virus (MDV), has a significant economic impact on the poultry industry due to its widespread prevalence and early exposure of chickens. The Meq gene is essential for MDV-induced tumor formation, particularly T cell tumors. Additionally, Ikaros gene has been identified as a key cancer driver gene in MDV tumorigenesis. The safety of recombinant MDV strain containing a wildtype Ikaros gene, was compared to the parental MDV and MD vaccines. While recombinant MDV with Ikaros exhibited significantly reduced virulence (tumor formation), it still caused immunosuppression through thymic and bursal atrophy. The pathogenicity of various MDV strains, including MDV with mutated Ikaros, MDV with Meq deletion plus wildtype or mutated Ikaros, was compared to parental MDV. Surprisingly, MDV with mutated Ikaros demonstrated the highest virulence, surpassing even the parental MDV strains in tumor formation, mortality, and disease incidence. Conversely, MDV with wildtype Ikaros exhibited reduced tumorigenicity and MD incidence. The deletion of Meq in MDV Ikaros viruses significantly reduced tumor formation. However, immunosuppression persisted in these strains, regardless of the Ikaros sequence (wildtype or mutated). In conclusion, MDV tumorigenicity is enhanced by Ikaros mutations, while the expression of ectopic wildtype Ikaros can suppress MDV-induced tumors.

Technical Abstract: Marek’s disease (MD) caused by the oncogenic avian herpesvirus, Marek’s disease virus (MDV) has significant economic impacts on the poultry industry because MDV is ubiquitous in the environment and most chickens are exposed the threat by MDV from the first day of age. Meq, a bZIP transac-tivator, is required for tumor formation by MDV, mostly T cell lymphomas. Additionally, Ikaros (IKZF1) has been identified as a cancer driver gene for MDV tumorigenesis. The safety of G2M-WT-Ikaros, which contains wildtype IKZF1 gene in the virulent MDV genome, was compared with the parental G2M and Rispens vaccine. Although G2M-WT-Ikaros has significantly reduced virulence (tumor formations), immunosuppression by the atrophies of thymus and bursa remained. The pathogenicity of G2M-WT-Ikaros and G2M-MUT-Ikaros (with Meq), G2M'MeqWT-Ikaros, and G2M'MeqMUT-Ikaros (without Meq) were compared with G2M viruses. Interestingly, G2M-MUT-Ikaros showed the highest virulence in tumor formation, mortality, and MD incidences, even higher than that of parental G2M viruses, while G2M-WT-Ikaros showed reduced tumor-igenicity and MD incidences. With Meq deletion, G2M'MeqWT-Ikaros, and G2M'MeqMUT-Ikaros virus significantly reduced tumor formations; however, the immunosuppression by those viruses still occurred, regardless of the different IKZF1 gene sequences, either wildtype or somatic mutated, in the MDV genome. Thus, MDV tumorigenicity by Meq gene is enhanced by IKZF1 mutations, but ectopic wildtype IKZF1 expression showed suppression of MDV-induced tumors.