Mutations in BTG1 Promote Germinal Center B-cell Malignant Transformation

Somatic hypermutation and proliferation rounds of germinal center (GC) B cells lead to the generation of high-affinity B-cell receptors, but these properties also put GC B cells at high risk for malignant transformation, with the most common neoplasm being diffuse large B-cell lymphoma (DLBCL). Somatic missense mutations in BTG1 are specific to GC-derived B-cell lymphomas, but how these mutations contribute to DLBCL pathogenesis has not been fully explored. Mlynarczyk and colleagues sought to evaluate the effects of BTG1 mutations on GC biology and malignant transformation and showed that BTG1 somatic mutations, most of which cluster around the N-terminus, are genetic drivers of DLBCL in which they confer a competitive fitness advantage during T cell–dependent immune responses specifically in the GC compartment. Evaluation of the competitive advantage conferred by Btg1 mutations revealed an enrichment of MYC and mTORC1 biosynthetic gene signatures as well as signatures associated with follicular helper T cell–induced light-zone-to-dark-zone (LZ-to-DZ) recycling of GC B cells (i.e., reentering the proliferative phase), with similar results being observed in human BTG1-mutant DLBCL samples. The association of BTG1 with MYC and other relevant transcripts involved in LZ-to-DZ recycling was blocked upon mutation of BTG1, and this was associated with a slightly lower threshold for MYC protein synthesis, which led to more cells expressing MYC. Moreover, Btg1-mutant LZ-to-DZ recycling GC B cells progressed through S phase more rapidly than control cells and entered the DZ proliferative program earlier and at greater proportions, leading to accelerated GC kinetics and an overall competitive fitness advantage. Furthermore, Btg1 mutation conferred a more aggressive and tissue-invasive phenotype to B-cell lymphomas in mice, and patients with BTG1-mutated DLBCL demonstrated inferior clinical outcomes. In summary, this work shows that mutations in BTG1 lead to “supercompetitor” GC B cells via only a subtle biochemical effect that results in a strikingly aggressive disease, which suggests that BTG1 is a critical gatekeeper in controlling B-cell fitness during the adaptive immune response.

Mlynarczyk C, Teater M, Pae J, Chin CR, Wang L, Arulraj T, et al.BTG1mutation yields supercompetitive B cells primed for malignant transformation. Science 2023;379:eabj7412.

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