Klhl6, a member of the KLHL gene family, functions as an E3 ligase gene. It assembles with cullin3 to form a cullin-RING ubiquitin ligase, playing a crucial role in the ubiquitin proteasome system which is essential for cellular homeostasis. KLHL6 is involved in multiple biological processes, with its function linked to pathways like the NF-κB pathway, and it has significance in B-cell development and lymphoma [1,3,4,5].

In diffuse large B-cell lymphoma (DLBCL), inactivation of Klhl6 promotes chemoresistance [2]. Mutations in Klhl6 disrupt its interaction with cullin3, leading to loss of function, and promote DLBCL growth and survival by stabilizing the mRNA decay factor roquin2 [1,5]. Also, Klhl6 deficiency impairs transitional B cell survival and differentiation, suggesting a delay in their differentiation process [4].

In conclusion, Klhl6 is essential in maintaining normal B-cell development and its function is critical in preventing DLBCL. The study of Klhl6 knockout models has provided insights into its role in B-cell-related diseases, helping to understand the molecular mechanisms underlying lymphoma development and potentially guiding new therapeutic strategies for DLBCL.

References:

1. Choi, Jaewoo, Zhou, Nan, Busino, Luca. 2019. KLHL6 is a tumor suppressor gene in diffuse large B-cell lymphoma. In Cell cycle (Georgetown, Tex.), 18, 249-256. doi:10.1080/15384101.2019.1568765. https://pubmed.ncbi.nlm.nih.gov/30646831/

2. Zhou, Nan, Choi, Jaewoo, Grothusen, Grant, Wan, Liling, Busino, Luca. . DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. In Blood, 142, 973-988. doi:10.1182/blood.2022018752. https://pubmed.ncbi.nlm.nih.gov/37235754/

3. Han, Lin, Chen, Zhenguo, Sun, Lei. 2023. Expression, purification, and microscopic characterization of the tumor suppressor KLHL6. In Protein expression and purification, 210, 106318. doi:10.1016/j.pep.2023.106318. https://pubmed.ncbi.nlm.nih.gov/37286065/

4. Bertocci, Barbara, Lecoeuche, Damiana, Sterlin, Delphine, Weill, Jean-Claude, Reynaud, Claude-Agnès. 2017. Klhl6 Deficiency Impairs Transitional B Cell Survival and Differentiation. In Journal of immunology (Baltimore, Md. : 1950), 199, 2408-2420. doi:10.4049/jimmunol.1700708. https://pubmed.ncbi.nlm.nih.gov/28807996/

5. Choi, Jaewoo, Lee, Kyutae, Ingvarsdottir, Kristin, Green, Michael R, Busino, Luca. 2018. Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2. In Nature cell biology, 20, 586-596. doi:10.1038/s41556-018-0084-5. https://pubmed.ncbi.nlm.nih.gov/29695787/