Abstract A024: SOX11: An <i>Achilles heel</i> of mantle cell lymphoma enhancing sensitivity to DNA damaging agents by impairing DNA repair
Bibliographic record
Abstract
Abstract Mantle cell lymphoma (MCL) is an aggressive malignancy with mature B-cell differentiation and a median overall survival of 5 years. A characteristic hallmark of MCL is the aberrant expression of the transcription factor sex determining region on Y chromosome (SRY)-related and high mobility group (HMG) domain containing protein 11 (SOX11) in approximately 90% of the cases. The role of SOX11 in MCL pathogenesis has been attributed to transcriptional dysregulation, ultimately driving malignant gene expression profile of MCL. However, little is known about the potential transcription factor-independent modes of action of SOX11. Our co-immunprecipitation and proteomic analysis showed that SOX11 binds to factors of DNA damage response (DDR), nucleosome remodeling and chromatin regulation, among others. Sterile Alpha motif and HD domain containing protein 1 (SAMHD1) is top-listed among the SOX11 binding partners in MCL. We recently showed that SOX11 binds via its HMG domain to SAMHD1, disturbing its homo-tetramerization. A growing body of evidence unveiled the implication of SAMHD1 in DDR, particularly in promoting homologous recombination. Immunofluorescent imaging showed that SOX11 impairs homologous recombination in MCL, evidenced by reduced accumulation of RAD51 foci upon chromatin in response to treatment with the topoisomerase1 inhibitor camptothecin (CPT). This was further consistent with abrogated phosphorylation of DNA-break binding protein RPA32 (S4/8), but not total RPA32, in response to CPT treatment in SOX11-positive conditions. Inducing SOX11 expression in SOX11-negative MCL cell line (JVM-2) resulted in increased accumulation of cytosolic single-stranded DNA upon CPT treatment. This was translated in an enhanced sensitivity to CPT in SOX11-expressing MCL cell lines as compared to SOX11-negative conditions. Moreover, this enhanced sensitivity was reflected in increased levels of cleaved PARP1, cleaved caspase 3 and persistent γ-H2A.X in SOX11-positive cells. Simian Immunodeficiency Virus protein (Vpx)-mediated depletion of SAMHD1 yielded a similar, yet attenuated, sensitive phenotype to CPT compared to SOX11 induction in JVM-2. SAMHD1 depletion in addition to SOX11 induction showed no significant additional impact on the response to CPT in JVM-2 under the conditions tested. Intriguingly, T592 phosphorylation of SAMHD1 was reduced upon inducing SOX11 expression in JVM-2, suggesting a mode of action by which SOX11 inhibits SAMHD1. However, the mechanism behind increased levels of SAMHD1 post-translational modification upon SOX11 induction requires further investigation. Altogether, our findings suggest that SOX11 may impair homologous recombination, at least in part, through inhibiting SAMHD1. These results highlight SOX11 as an Achilles heel that renders MCL vulnerable to DNA damaging and suggest that incorporating DNA damaging agents including topoisomerase inhibitors or anthracyclines into currently used treatment modalities for MCL might be clinically beneficial. Citation Format: HA Morsy, Virginia Amador, Birger Christensson, Nikolas Herold, Birgitta Sander. SOX11: An Achilles heel of mantle cell lymphoma enhancing sensitivity to DNA damaging agents by impairing DNA repair [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A024.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".