GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma.

Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.

Identification of genetic subtypes in follicular lymphoma.

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Single gene mutations and prognosis in limited-stage follicular lymphoma treated with radiation therapy.

Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.

Impact of myocardial perfusion imaging with PET and (82)Rb on downstream invasive procedure utilization, costs, and outcomes in coronary disease management.

UNLABELLED: We hypothesized that PET myocardial perfusion imaging with (82)Rb (PET MPI), would reduce downstream utilization of diagnostic arteriography, compared with SPECT, in patients matched for pretest likelihood of coronary disease (pCAD). PET MPI is more accurate for assessment of impaired coronary flow reserve compared with SPECT MPI, potentially reducing the demand for subsequent arteriography, percutaneous trans-coronary intervention, and coronary artery bypass grafting (CABG), with attendant cost savings, while avoiding a negative impact on coronary events. METHODS: The frequency of diagnostic arteriography, revascularization, costs, and 1-y clinical outcomes in 2,159 patients studied with PET MPI was compared with 2 control groups studied with SPECT MPI matched to the PET group by pCAD: an internal control group of 102 patients and an external SPECT control group of 5,826 patients. CAD management costs were approximated with realistic global fee estimates. RESULTS: Arteriography rates were 0.34 and 0.31 for the external and internal control SPECT groups and 0.13 for the patients studied with PET (P < 0.0001). pCAD averaged 0.39 in patients studied with PET MPI, and in the external SPECT control group, and 0.37 in the internal SPECT controls. Revascularization rates were 0.13 and 0.11 for external and internal SPECT patients and 0.06 for the PET group (P < 0.0001; P < 0.01), with a cost savings of 30% noted for PET patients, with no significant difference in cardiac death or myocardial infarction at 1-y follow-up. CONCLUSION: PET MPI in patients with intermediate pCAD results in a >50% reduction in invasive coronary arteriography and CABG, a 30% cost savings, and excellent clinical outcomes at 1 y compared with SPECT.