Bcl6, also known as B-cell lymphoma 6, is a transcriptional repressor that plays a crucial role in the development and maintenance of germinal centers (GCs), which are essential for an effective humoral immune response [2,5]. It is involved in regulating the development and function of multiple immune cell types such as GC B cells, follicular helper T (Tfh) cells, follicular regulatory T (Tfr) cells, and immune memory cells [5]. Bcl6 also has functions outside the immune system, and its gene is significant in human oncology [5]. Genetic models, like KO/CKO mouse models, are valuable for studying Bcl6's functions.

In placental and endometrial tissues, Bcl6 is important in cell proliferation, survival, differentiation, migration, and invasion of trophoblastic cells [1]. Its aberrant up-regulation in pre-eclamptic placentas and endometriotic lesions is associated with the pathogenesis of pre-eclampsia (PE) and endometriosis [1]. In B-cell non-Hodgkin lymphomas (B-NHL), genomic aberrations of Bcl6 lead to its sustained activity, promoting lymphoma development, and thus, inhibiting Bcl6 is an attractive therapeutic strategy [2]. In gastrointestinal stromal tumor (GIST), Bcl6 expression is induced by imatinib treatment, suppressing apoptosis and contributing to drug resistance [3]. Deletion of Bcl6 in mice redefines our understanding of innate lymphoid cell 3 (ILC3) subset biology, as it dysregulates the lymphoid tissue inducer (LTi)-like ILC3 transcriptional program and enhances interleukin-17A (IL-17A) and IL-17F expression in LTi-like ILC3s [4]. In Mantle cell lymphoma (MCL), Bcl6+ MCL has a significantly shorter overall survival and higher Ki67 proliferation index, indicating its prognostic value [6]. In pediatric cancers, Bcl6 acts as a proto-oncogene, driving the self-renewal capacity of leukemia-initiating cells and associated with disease progression and treatment resistance [7].

In conclusion, Bcl6 is a key regulator in immune cell development and function, and its dysregulation is associated with various diseases including reproductive disorders, lymphomas, GIST, and pediatric cancers. The use of KO/CKO mouse models has significantly contributed to understanding Bcl6's role in these disease conditions, providing insights into potential therapeutic strategies targeting Bcl6.

References:

1. Louwen, Frank, Kreis, Nina-Naomi, Ritter, Andreas, Solbach, Christine, Yuan, Juping. . BCL6, a key oncogene, in the placenta, pre-eclampsia and endometriosis. In Human reproduction update, 28, 890-909. doi:10.1093/humupd/dmac027. https://pubmed.ncbi.nlm.nih.gov/35640966/

2. Leeman-Neill, Rebecca J, Bhagat, Govind. 2018. BCL6 as a therapeutic target for lymphoma. In Expert opinion on therapeutic targets, 22, 143-152. doi:10.1080/14728222.2018.1420782. https://pubmed.ncbi.nlm.nih.gov/29262721/

3. Zeng, Xiangyu, Zhao, Fei, Jia, Jie, Lou, Zhenkun, Zhang, Peng. . Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib. In Cancer research, 83, 3624-3635. doi:10.1158/0008-5472.CAN-23-0082. https://pubmed.ncbi.nlm.nih.gov/37556508/

4. Tachó-Piñot, Roser, Stamper, Christopher T, King, James I, Withers, David R, Hepworth, Matthew R. 2023. Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3. In Cell reports, 42, 113425. doi:10.1016/j.celrep.2023.113425. https://pubmed.ncbi.nlm.nih.gov/37950867/

5. Liongue, Clifford, Almohaisen, Farooq L J, Ward, Alister C. 2024. B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond. In International journal of molecular sciences, 25, . doi:10.3390/ijms252010968. https://pubmed.ncbi.nlm.nih.gov/39456751/

6. Castillo, Dani Ran, Park, Daniel, Jeon, Won Jin, Zhang, Ke K, Cao, Huynh. 2023. Unveiling the Prognostic Significance of BCL6+/CD10+ Mantle Cell Lymphoma: Meta-Analysis of Individual Patients and Systematic Review. In International journal of molecular sciences, 24, . doi:10.3390/ijms241210207. https://pubmed.ncbi.nlm.nih.gov/37373354/

7. McLachlan, Tabitha, Matthews, William C, Jackson, Evangeline R, Germon, Zacary P, Dun, Matthew D. . B-cell Lymphoma 6 (BCL6): From Master Regulator of Humoral Immunity to Oncogenic Driver in Pediatric Cancers. In Molecular cancer research : MCR, 20, 1711-1723. doi:10.1158/1541-7786.MCR-22-0567. https://pubmed.ncbi.nlm.nih.gov/36166198/