Expression of cyclin D1 () is required for cancer cell survival and proliferation. This is presumably due to the role of cyclin D1 in inactivation of the RB tumor suppressor. Here, we investigated the pro-survival function of cyclin D1 in a number of cancer cell lines. We found that cyclin D1 depletion facilitated cellular senescence in several cancer cell lines. Senescence triggered by cyclin D1 depletion was more extensive than that caused by the prolonged CDK4 inhibition. Intriguingly, the senescence caused by cyclin D1 depletion was independent of RB status of the cancer cell. We identified a build-up of intracellular reactive oxygen species in the cancer cells that underwent senescence upon depletion of cyclin D1 but not in those cells where CDK4 was inhibited. The higher ROS levels were responsible for the cell senescence, which was instigated by the p38-JNK-FOXO3a-p27 pathway. Therefore, expression of cyclin D1 prevents cancer cells from undergoing senescence, at least partially, by keeping the level of intracellular oxidative stress at a tolerable sub-lethal level. Depletion of cyclin D1 promotes the RB-independent pro-senescence pathway and the cancer cells then succumb to the endogenous oxidative stress levels.This article has an associated First Person interview with the first author of the paper.

Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators that regulate these key cellular programs in CRC, we developed an endogenous reporter system by genome-editing human CRC cell lines with knock-in fluorescent reporters at the SOX9 and KRT20 locus to report aberrant stem cell-like activity and differentiation respectively in pooled CRISPR screening formats. We then constructed a dual reporter system that simultaneously monitors aberrant stem cell-like and differentiation activity in the same CRC cell line, improving our signal to noise discrimination. Using a focused-library CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs, we identified factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominated SMARCB1 of the SWI/SNF BAF complex as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency in CRC and required for human CRC cell line and patient-derived organoid growth in vivo. These studies highlight the utility of a biologically designed endogenous reporter system to uncover novel therapeutic targets for drug development.

Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of cutaneous T cell lymphoma. Despite its higher prevalence in Asia than other regions, the clinicopathological data of SPTCL in Asian population is scarce. Materials and Methods: Patients who were diagnosed with SPTCL in Siriraj Hospital, Thailand, from 2010 to 2021 were identified. Demographic, clinical, and laboratory data were retrospectively collected from the hospital database. All statistics were performed in IBM SPSS Statistics Version 23. All continuous variables were reported as medians and their associated ranges. Results: A total of 48 patients, comprising of 13 males and 35 females, were included in this study. The median age of the cohort was 30 years old. Seven (14.6%) patients had previous or concurrent autoimmune diseases. Seven (14.6%) patients presented with concomitant hemophagocytic lymphohistiocytosis (HLH) at diagnosis. Out of 14 patients who were tested for T-cell receptor (TCR) gene rearrangement, 9 were positive for at least one of monoclonal TCR-β, -γ, or -δ gene rearrangement. The summary of characteristics, presentations, and laboratory results of patients were shown in Table 1. 34 and 14 patients received immunosuppressant therapy (IMT) and chemotherapy (CMT) as their first line of treatment, respectively. The response rates were comparable in both groups. Conclusions: Clinical presentations of SPTCL in patient's cohort in Asian population are similar to those reported in Western population except a higher rate of autoimmune features. IMT and CMT resulted in similar short-term outcome. Further studies on long-term outcome and the predictive markers for treatment response will be beneficial for this rare subtype of T-cell lymphoma. Figure 1 Figure 1. Disclosures Khuhapinant: Astellas Pharma, Inc.: Research Funding.