Identifying gene signatures contributing to progression after chemotherapy in DLBCL patients

Lymphoma is a cancer that begins in the lymphocyte cells of the immune system. There are over 60 different types, broadly grouped into Hodgkin lymphomas and non-Hodgkin lymphomas. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma. The primary treatment for DLBCL is R-CHOP (Rituximab, Cyclophosphamide, doxorubicin hydrochloride (Hydroxy daunomycin), Oncovin, and Prednisone) chemotherapy. However, even after the treatment, only 50-60% of patients show complete response; the remaining patients suffer from progression in the form of relapse (cancer reappearing) and refractory disease (cancer stops responding to treatment)

Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL

DLBCL is the most common lymphoma with high tumor heterogeneity. Treatment refractoriness and relapse from R-CHOP therapy in patients remain a clinical problem. Activation of the non-canonical NF-κB pathway is associated with R-CHOP resistance. However, downstream targets of non-canonical NF-κB mediating R-CHOP-induced resistance remains uncharacterized. Here, we identify the common mechanisms underlying both intrinsic and acquired resistance that are induced by doxorubicin, the main cytotoxic component of R-CHOP. We performed global transcriptomic analysis of (1) a panel of resistant versus sensitive and (2) isogenic acquired doxorubicin-resistant DLBCL cell lines following short and chronic exposure to doxorubicin respectively. Doxorubicin-induced stress in resistant cells activates a distinct transcriptional signature that is enriched in metabolic reprogramming and oncogenic signalling. Selective and sustained activation of non-canonical NF-κB signalling in these resistant cells exacerbated their survival by augmenting glycolysis. In response to doxorubicin, p52-RelB complexes transcriptionally activated multiple glycolytic regulators with prognostic significance through increased recruitment at their gene promoters. Targeting p52-RelB and their targets in resistant cells increased doxorubicin sensitivity in vitro and in vivo. Collectively, our study uncovered novel molecular drivers of doxorubicin-induced resistance that are regulated by non-canonical NF-κB pathway. We reveal new avenues of therapeutic targeting for R-CHOP-treated refractory/relapsed DLBCL patients.Nanyang Technological UniversityNational Medical Research Council (NMRC)National Research Foundation (NRF)Submitted/Accepted versionThis study is funded by the National Research Foundation (NRF) Singapore, under its Singapore NRF Fellowship (NRFNRFF2018-04). In addition, we thank the Nanyang Assistant Professorship (NAP) Startup-grant to Y.L. lab and National Medical Research Council (NMRC-OFLCG18May0028), Tanoto Foundation and Ling Foundation for their support

Protist.guru: a comparative transcriptomics database for protists

During the last few decades, the study of microbial ecology has been enabled by molecular and genomic data. DNA sequencing has revealed the surprising extent of microbial diversity and how microbial processes run global ecosystems. However, significant gaps in our understanding of the microbial world remain, and one example is that microbial eukaryotes, or protists, are still largely neglected. To address this gap, we used gene expression data from 17 protist species to create protist.guru: an online database equipped with tools for identifying co-expressed genes, gene families, and co-expression clusters enriched for specific biological functions. Here, we show how our database can be used to reveal genes involved in essential pathways, such as the synthesis of secondary carotenoids in Haematococcus lacustris. We expect protist.guru to serve as a valuable resource for protistologists, as well as a catalyst for discoveries and new insights into the biological processes of microbial eukaryotes. AVAILABILITY: The database and co-expression networks are freely available from http://protist.guru/. The expression matrices and sample annotations are found in the supplementary data.Submitted/Accepted versio