In:
Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6629 ( 2023-01-20)
Abstract:
Diffuse large B cell lymphomas (DLBCLs) are aggressive malignancies of which ~40% fail to respond or become refractory to treatment. Mechanisms that mediate these poor outcomes are unknown. Most DLBCLs originate from specialized B cells participating in the germinal center (GC) reaction. GCs are transient structures within which antigen-activated B cells undergo proliferative bursting and somatic hypermutation of their immunoglobulin genes to improve affinity against the encountered antigen. High proliferation activity depletes GC B cells of essential biosynthetic precursors. Hence, GC B cells must endure an intense Darwinian competition process, during which they vigorously compete for access to positive selection signals from a limiting number of T follicular helper (T FH ) cells. Only few B cells that win this competition receive T FH cell help, which triggers transient expression of the Myc proto-oncogene and biosynthetic growth programs. Unfortunately, GC B cells acquire abundant off-target mutations, making them prone to malignant transformation. Hence, GC B cell selection by T FH cells requires rigorous, but still largely unknown, control mechanisms to prevent unwanted clonal expansion and malignant transformation of abnormal cells. RATIONALE Missense mutations of BTG1 (B cell translocation gene 1) are specific to GC-derived B cell lymphomas, suggesting that their oncogenic function is cell-context specific. BTG1 mutations help to genetically define a class of DLBCLs that manifest especially poor clinical outcomes and extensive dissemination. This prompted us to explore how BTG1 mutations contribute to the pathogenesis of these clinically challenging tumors. RESULTS We generated mice for the B cell–conditional expression of the most frequent BTG1 mutation [Gln 36 →His (Q36H)]. Btg1 Q36H cells almost completely outcompeted their wild-type counterparts, specifically in the GC. This competitive fitness manifested as a stronger induction of MYC-dependent growth programs. Wild-type BTG1 associated with many mRNAs, including those for MYC and MYC target genes, a function that was significantly lost by BTG1 Q36H . Mutant BTG1 expression enhanced MYC mRNA loading onto polysomes and induced slightly more-rapid MYC protein induction kinetics and a higher fraction of MYC-positive B cells in murine and human systems. These data suggested a lower threshold for BTG1 mutant cells to respond to T FH -positive selection signals. Accordingly, Btg1 mutant GC B cells experienced faster cell cycle S phase transit and earlier entry into subsequent proliferative bursts. In Bcl2-driven lymphoma mouse models, Btg1 Q36H markedly accelerated disease onset, shortened survival, and yielded particularly invasive DLBCL-like lymphomas. Btg1 Q36H lymphomas were highly clonal and heavily mutated, reflecting a lymphomagenesis trajectory with increased selection and mutation rounds over time. In patients, BTG1 mutations scored as strong genetic DLBCL drivers and independently associated with significantly inferior clinical outcomes. CONCLUSION Our data suggest that BTG1 serves as a critical gatekeeper controlling a key fitness checkpoint for natural selection of intensely competing B cells during the adaptive immune response. The precise targeting of BTG1 function by missense mutations causes a subtle biochemical impact, whose specific engagement during repetitive rounds of GC B cell positive selection likely explains its substantial oncogenic fitness effect. This reveals the fragility of constraints required to prevent competing B cells from recalling features of uncontrolled natural selection among unicellular organisms and highlights a fine-tuned balance between protection against infection and cancer risk. This effect is reminiscent of the Myc-dependent supercompetition first described during Drosophila development. Future therapeutic strategies could potentially take advantage of such evolutionary vulnerabilities to target cancer cell fitness. Supercompetition in germinal centers leads to aggressive B cell lymphomas. GC B cells vigorously compete against each other to receive limiting T cell help, which activates MYC-dependent growth programs in preparation for subsequent proliferative bursting. BTG1 mutant GC B cells respond to T cell help signals with faster MYC induction kinetics and more-rapid entry into the next proliferative phase, which, over many GC rounds, allows them to outcompete wild-type cells, leading to highly fit and disseminated B cell lymphomas. ILLUSTRATION: CEYDA DURMAZ
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abj7412
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2023
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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