The spliceosome component Usp39 controls B cell development by regulating immunoglobulin gene rearrangement

• Published in: Cell reports (Cambridge) Vol. 38; no. 6; p. 110338
• Main Authors: Ruan, Gui-Xin, Li, Yuxing, Chen, Wenjing, Huang, Hengjun, Zhang, Rui, Chen, Changxu, Lam, Kong-Peng, Xu, Shengli, Ou, Xijun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.02.2022; Elsevier
• Subjects: Animals; B cell development; B-Lymphocytes - cytology; chromatin interaction; Genes, Immunoglobulin - genetics; Humans; immunoglobulin gene rearrangement; lymphoma; Mice; Ribonucleoprotein, U4-U6 Small Nuclear - genetics; Ribonucleoprotein, U5 Small Nuclear - metabolism; RNA Precursors - metabolism; spliceosome; Spliceosomes - metabolism; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; Usp39; chromatin interaction; Usp39; spliceosome; B cell development; immunoglobulin gene rearrangement; lymphoma
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110338

The spliceosome is a large ribonucleoprotein complex responsible for pre-mRNA splicing and genome stability maintenance. Disruption of the spliceosome activity may lead to developmental disorders and tumorigenesis. However, the physiological role that the spliceosome plays in B cell development and function is still poorly defined. Here, we demonstrate that ubiquitin-specific peptidase 39 (Usp39), a spliceosome component of the U4/U6.U5 tri-snRNP complex, is essential for B cell development. Ablation of Usp39 in B cell lineage blocks pre-pro-B to pro-B cell transition in the bone marrow, leading to a profound reduction of mature B cells in the periphery. We show that Usp39 specifically regulates immunoglobulin gene rearrangement in a spliceosome-dependent manner, which involves modulating chromatin interactions at the Igh locus. Moreover, our results indicate that Usp39 deletion reduces the pre-malignant B cells in Eμ-Myc transgenic mice and significantly improves their survival. [Display omitted] •Usp39 is essential for early B cell development in the bone marrow•Usp39 regulates immunoglobulin gene rearrangement in a spliceosome-dependent manner•Usp39 modulates chromatin interaction at the Igh locus•Deletion of Usp39 mitigates B cell lymphomagenesis in Eμ-Myc transgenic mice Ruan et al. report that the spliceosome component Usp39 is essential for B cell development by regulating immunoglobulin gene rearrangement. These results suggest that Usp39 could be a potential therapeutic target for B cell lymphomas