Blk, also known as B-cell lymphocyte kinase or B-lymphoid tyrosine kinase, is a member of the SRC family nonreceptor tyrosine kinase. It is involved in the B-cell receptor (BCR) signaling pathway, playing a crucial role in B cell development and function. Dysregulation of Blk is associated with autoimmune diseases and cancer [2,4].

BLK-deficient mice produce less inflammatory cytokines and are more resistant to death upon IL-1β challenge, indicating that BLK positively regulates TLR/IL-1R-mediated inflammatory response. Mechanistically, IL-1β stimulation triggers BLK autophosphorylation, which then phosphorylates TOLLIP, promoting its dissociation from IRAK1 and facilitating TLR/IL-1R-mediated signal transduction [1]. BLK-deficient mice also exhibit lower serum cytokine levels and higher lethality after VSV infection, and BLK deficiency impairs the secretion of downstream antiviral cytokines and promotes Senecavirus A (SVA) proliferation. Viral infection triggers BLK autophosphorylation, which then phosphorylates IRF3, facilitating its sufficient activation and downstream antiviral response [5]. In addition, in R-CHOP treated diffuse large B-cell lymphoma, BLK expression in tumor cells was significantly associated with the expression of both C-MYC and BCL2, and BLK positivity was an independent poor prognostic factor [3].

In conclusion, Blk is essential for regulating inflammatory and antiviral responses, and its dysregulation is related to diseases like lymphoma. The study of Blk-deficient mouse models has provided valuable insights into its role in these biological processes and disease conditions, highlighting its potential as a therapeutic target for related diseases.

References:

1. Li, Wei-Wei, Fan, Xu-Xu, Xu, Zhi-Sheng, Wang, Yan-Yi, Zheng, Hai-Xue. 2023. BLK positively regulates TLR/IL-1R signaling by catalyzing TOLLIP phosphorylation. In The Journal of cell biology, 223, . doi:10.1083/jcb.202302081. https://pubmed.ncbi.nlm.nih.gov/38078859/

2. Kohal, Rupali, Kumari, Preety, Sharma, Arun Kumar, Gupta, Ghanshyam Das, Verma, Sant Kumar. 2024. Fyn, Blk, and Lyn kinase inhibitors: A mini-review on medicinal attributes, research progress, and future insights. In Bioorganic & medicinal chemistry letters, 102, 129674. doi:10.1016/j.bmcl.2024.129674. https://pubmed.ncbi.nlm.nih.gov/38408513/

3. Choi, Soyeon, Lee, Yoo Jin, Choi, Yunsuk, Cha, Hee Jeong, Jo, Jae-Cheol. 2022. Prognostic significance of BLK expression in R-CHOP treated diffuse large B-cell lymphoma. In Journal of pathology and translational medicine, 56, 281-288. doi:10.4132/jptm.2022.07.26. https://pubmed.ncbi.nlm.nih.gov/36128864/

4. Fu, Tiancheng, Zuo, Yingying, Zhong, Zhenpeng, Chen, Xuan, Pan, Zhengying. 2021. Discovery of selective irreversible inhibitors of B-Lymphoid tyrosine kinase (BLK). In European journal of medicinal chemistry, 229, 114051. doi:10.1016/j.ejmech.2021.114051. https://pubmed.ncbi.nlm.nih.gov/34952433/

5. Li, Wei-Wei, Fan, Xu-Xu, Zhu, Zi-Xiang, Wang, Yan-Yi, Zheng, Hai-Xue. 2023. Tyrosine phosphorylation of IRF3 by BLK facilitates its sufficient activation and innate antiviral response. In PLoS pathogens, 19, e1011742. doi:10.1371/journal.ppat.1011742. https://pubmed.ncbi.nlm.nih.gov/37871014/