Abstract B012: Bromodomain and extra-terminal domain (BET) as a therapeutic target in a mouse model of secondary hemophagocytic lymphohistiocytosis (HLH)
Bibliographic record
Abstract
Abstract Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory syndrome triggered by autoimmune disease, infection, or malignancy. It involves a defective cytotoxic lymphocyte response that fails to eliminate the trigger, leading to sustained IFNγ secretion and myeloid effector cell activation, causing tissue damage. BET proteins bind acetylated histones and regulate gene transcription. BET inhibitor OPN-51107 selectively blocks BRD4 activity. We evaluated BET inhibition in a murine model of secondary HLH induced in C57BL/6 mice by repeated CpG 1826 and anti-IL-10 receptor antibody injections. Mice with HLH develop weight loss, cytopenia, hepatosplenomegaly, and cytokine storm. Mice were randomized to three groups: healthy control, HLH treated with vehicle, or HLH treated with OPN-51107 (10 mg/kg/day orally starting on day 4). On day 9, mice were sacrificed. Organ weights and blood counts were recorded. Spleenocytes were analyzed by flow cytometry. Plasma IFN-γ, IL-6, and IL-18 were measured by ELISA. Statistical analysis was performed using one-way ANOVA. Vehicle-treated mice developed hepatomegaly (p <0.0001) and splenomegaly (p <0.0001) compared to healthy controls, while OPN-51107-treated mice showed a significant reduction in both liver and spleen enlargement compared to vehicle-treated (liver p=0.0009, spleen p <0.0001). Anemia is a hallmark of HLH. Red blood cell count was significantly reduced in vehicle-treated HLH mice compared to healthy controls (p < 0.0001) but significantly improved with BET inhibitor treatment (p=0.0035). Plasma IFN-γ and IL-6 were elevated in vehicle-treated HLH mice (IFN-γ p=0.0003; IL-6 p < 0.0001) but returned to baseline or were significantly lowered in BET inhibitor–treated HLH mice (IFN-γ p=0.0156; IL-6 p=0.0002). Similarly, IL-18 levels rose in vehicle-treated HLH mice (p <0.0001), but reduced in mice with HLH treated with BET inhibitor (p=0.0375). HLH caused expansion of splenic myeloid cells (CD4-/CD8-/CD11b+, p=0.0308), particularly neutrophils (CD11b+/Ly6C+/Ly6G+, p<0.0001), and depletion of CD4+ T cells (p<0.0001) in vehicle-treated mice versus healthy controls. BET inhibitor treatment restored these populations significantly (CD11b+, p=0.0377; CD4+, p=0.0140). Additionally, intracellular TNF-α in myeloid cells was markedly increased in vehicle-treated HLH mice compared to both healthy controls (p <0.0001) and OPN-51107–treated HLH mice (p = 0.0002). These findings demonstrate that BET inhibition alleviates key inflammatory features in murine HLH and highlights BET inhibition as a potential therapeutic strategy, warranting further mechanistic investigation. Citation Format: Paola Marra, Rathan Kumar, Charlene Mao, Sydney Leon, Ian Haut, Robert Baiocchi, Parvathi Ranganathan, Polina Shindiapina. Bromodomain and extra-terminal domain (BET) as a therapeutic target in a mouse model of secondary hemophagocytic lymphohistiocytosis (HLH) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B012.
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How this classification was reachedexpand
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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".