Abstract A24: <i>BTG1</i> mutations confer a fitness advantage and promote aggressive B cell lymphoma development by lowering the threshold for MYC induction
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Bibliographic record
Abstract
Abstract BTG1 somatic mutations are exclusively found in mature B cell malignancies, ~12% diffuse large B cell lymphoma (DLBCL) and are particularly enriched in the MCD/cluster 5 subtype of ABC-DLBCL, characterized by extranodal dissemination and poor clinical outcome. However, the mechanism of action and clinical relevance of BTG1 mutations remain unknown. We find that BTG1 mutations score among the top mutations with DLBCL driver potential, using a rigorous genomic and epigenomic covariates analysis. Most notably, BTG1 mutant patients presented with inferior clinical outcome (p=0.0011) in ABC-DLBCL cases from 5 cohorts and BTG1 mutation was independently associated with lower overall survival in a multivariable Cox regression analysis (p=0.0190) DLBCL originates from mature B cells having experienced the germinal center (GC) reaction. We therefore generated a conditional knockin mouse model to express the most frequent Btg1 Q36H in B cells. Btg1 Q36H GC B cells showed a dramatic fitness advantage in in vivo competitive assays. This effect was specific to the GC compartment and was dependent on T cells. RNAseq showed that Btg1Q36H GC B cells were markedly enriched for genes normally transiently induced upon positive selection by T cells, including MYC targets. The same signatures were enriched in BTG1 mutant DLBCL patients and isogenic BTG1Q36H vs BTG1WT human DLBCL cell lines. We observed a higher proportion of MYC-expressing cells in Btg1Q36H GCs without an increase in maximal MYC levels per cell, also confirmed in human DLBCL lines and primary human tonsillar B cells, suggesting a lowered threshold for MYC induction in mutant cells. Mechanistically, ~800 transcripts associated with BTG1WT, but not BTG1Q36H. These belong to the same gene sets that characterize positively selected GC B cell, including MYC itself. BTG1Q36H therefore showed reduced association with the MYC mRNA. We found that this associated with facilitated MYC protein synthesis. Polysome profiling also showed higher translation capacity in BTG1Q36H DLBCL cells. Crossing our Btg1 Q36H mice to the VavP-Bcl2 model showed that VavP-Bcl2+Btg1Q36H mice displayed shorter survival, earlier onset of lymphoma and dysplastic B cell infiltration into non lymphoid organs. Immunoglobulin genes sequencing showed that VavP-Bcl2+Btg1Q36H lymphoma B cells were highly clonal, extensively mutated and selected. Importantly, the lack of BTG1 deletions suggested that BTG1 missense mutations do not cause a full loss-of-function of the protein. Indeed, we observed that shRNA-mediated knockdown of BTG1 resulted in apoptosis. Collectively, BTG1 mutations contribute to the formation of aggressive lymphomas through an entirely novel mechanism, by lowering the threshold to MYC induction in response to T cell selection signals, conferring dramatic fitness. This effect appears to correspond to a partial loss of function disrupting a novel GC context-specific check point, whereby BTG1 normally attenuates spurious MYC translation to tightly restrict fitness potential. Citation Format: Coraline Mlynarczyk, Matt Teater, Juhee Pae, Ling Wang, Jonatan Ersching, Antonin Papin, Darko Barisic, Ersilia Barin, Kenneth B. Hoehn, Zhengming Chen, Diu T. T. Nguyen, Chiara Evans, Ashley S. Doane, Michael G. Kharas, David W. Scott, Gabriel Victora, Ari Melnick. BTG1 mutations confer a fitness advantage and promote aggressive B cell lymphoma development by lowering the threshold for MYC induction [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A24.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it