Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPC) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a pre-malignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation attenuated. We also document that CREBBP mutations may occur in HSPC from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid-transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

Galectins are a family of lectin binding proteins expressed both intracellularly and extracellularly. Galectin-3 (Gal-3, also known as LGALS3) is expressed at the cell surface; however, Gal-3 lacks a signal sequence, and the mechanism of Gal-3 transport to the cell surface remains poorly understood. Here, using a genome-wide CRISPR/Cas9 forward genetic screen for regulators of Gal-3 cell surface localization, we identified genes encoding glycoproteins, enzymes involved in N-linked glycosylation, regulators of ER-Golgi trafficking and proteins involved in immunity. The results of this screening approach led us to address the controversial role of N-linked glycosylation in the transport of Gal-3 to the cell surface. We find that N-linked glycoprotein maturation is not required for Gal-3 transport from the cytosol to the extracellular space, but is important for cell surface binding. Additionally, secreted Gal-3 is predominantly free and not packaged into extracellular vesicles. These data support a secretion pathway independent of N-linked glycoproteins and extracellular vesicles.

Introduction This study aimed to investigate potential factors, including delay to surgical stabilisation, affecting mortality in older patients sustaining pelvic or acetabular (PA) fractures. Materials and methods A retrospective review of the Trauma Audit and Research Network (TARN) database was performed to identify older patients (aged 65 and over) sustaining PA fractures treated surgically in a UK Major Trauma Centre (MTC) between 2015 and 2019. Chi-squared and Fisher tests were used to compare 1-year mortality rates following operative intervention between patients treated within 72 h and after 72 h. Kaplan–Meier curves were used to visualise survival probability; significant predictors of survival were found using Cox proportional hazard models. Results Of 564 older patients with PA fractures, 70 met the inclusion criteria. The mean age was 76.1 years. The overall 1-year mortality rate was 20%. When patients were grouped by time to surgery (fracture fixation within or greater than 72 h), there was no statistically significant difference in 1-year mortality. Patients whose surgery was delayed more than 72 h were more likely to have longer hospital stays (p = 0.002) or to have suffered from polytrauma (p = 0.025). Age, Charlson Co-morbidities Index (CCI) and pre-op mobility status were associated with statistically significant differences in overall mortality. The same factors were associated with a significantly increased hazard of death in the multivariate Cox proportional hazards model. Patient gender, mechanism of injury, Injury Severity Score (ISS) > 15 and head injury were not significant predictors of mortality. Conclusion Surgical intervention within 72 h of injury did not result in decreased mortality in older patients with PA fractures. The 1-year mortality rate between older PA fractures and hip fractures was comparable. Consideration should be given to a combined multidisciplinary approach between orthogeriatric and expert PA surgeons for these patients.