Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma.

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC, which is abnormally highly expressed in ~70% of human cancers, we use a genome-wide CRISPR gene knockout screen in Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discover that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerates c-MYC-driven lymphoma development in mice.

Charting New Paths in Cancer Research: Insights from the Frontiers in Cancer Science Conference 2024.

The 16th annual Frontiers in Cancer Science conference convened leading experts to discuss the latest developments in cancer research. Key research themes included mechanisms of treatment resistance and innovative strategies to target resistant cancer cells, metabolic plasticity and its therapeutic vulnerabilities, modulation of the tumor microenvironment to enhance therapeutic efficacy, recent advances in immunotherapies and engineered immune cells, and strategies to overcome tumor immune evasion. The conference also highlighted the development of advanced spatial transcriptomic technologies as a powerful tool to decipher tumor heterogeneity and identify novel therapeutic targets.

The transcription complex p52-ETS1 is essential for germinal center formation.

The NF-κB family comprises five transcription factors (RELA, RELB, C-REL, NF-κB1 (p50) and NF-κB2 (p52)) that form homo- or heterodimers among themselves to regulate gene expression by binding DNA. Here we show that p52 activates transcription without directly binding DNA but as a heterotetrameric complex with ETS1, a transcription factor outside the NF-κB family. By generating a knock-in mouse model (Nfkb2) with three mutated residues on p52 required for its interaction with ETS1, but not RELB, we demonstrate that the p52-ETS1 complex regulates the expression of transcription factors OCT1 and OBF1, which are known to be critical for the germinal center program.

Prospective Clinical Validation of a Combinatorial Functional Precision Medicine Platform in Relapsed/Refractory Non-Hodgkin's Lymphoma.

Purpose: Despite initially responding to first-line treatment, many patients with non-Hodgkin's lymphoma (NHL) eventually relapse or are refractory. These patients are empirically subjected to salvage therapies that may not be efficacious. We had previously presented feasibility evidence of an ex vivo functional precision medicine (FPM) platform, quadratic phenotypic optimization platform (QPOP), being potentially useful in identifying alternative therapeutic options for patients with relapsed/refractory (R/R)-NHL.

Aggressive B-cell lymphomas retain ATR-dependent determinants of T-cell exclusion from the Germinal Center Dark Zone.

The germinal center (GC) dark zone (DZ) and light zone (LZ) represent distinct anatomical regions in lymphoid tissue where B-cell proliferation, immunoglobulin diversification, and selection are coordinated. Diffuse Large B-cell Lymphomas (DLBCL) with DZ-like gene expression profiles exhibit poor outcomes, though reasons are unclear and are not directly related to proliferation. Physiological DZs exhibit an exclusion of T-cells, prompting exploration for whether T-cell paucity contributes to DZ-like DLBCL.

MS CETSA deep functional proteomics uncovers DNA repair programs leading to gemcitabine resistance.

Mechanisms for resistance to cytotoxic cancer drugs are dependent on dynamic changes in the biochemistry of cellular pathways, information which is hard to obtain at the systems level. Here we use a deep functional proteomics implementation of the Cellular Thermal Shift Assay to reveal a range of induced biochemical responses to gemcitabine in resistant and sensitive diffuse large B cell lymphoma cell lines. Initial responses in both, gemcitabine resistant and sensitive cells, reflect known targeted effects by gemcitabine on ribonucleotide reductase and DNA damage responses.

Single-cell Resolved Oncogene Co-expression: From Principles to Clinical Impact.

This commentary explores the concept and utility of studying oncogene co-expression at single-cell resolution and its clinical and biological implications. We emphasize the importance of scalable methods, mathematically driven quantification models, and artificial intelligence integration to enhance the clinical utility of this approach.

A multi-task domain-adapted model to predict chemotherapy response from mutations in recurrently altered cancer genes.

Next-generation sequencing (NGS) is increasingly utilized in oncological practice; however, only a minority of patients benefit from targeted therapy. Developing drug response prediction (DRP) models is important for the "untargetable" majority. Prior DRP models typically use whole-transcriptome and whole-exome sequencing data, which are clinically unavailable.

ColocZStats: a z-stack signal colocalization extension tool for 3D slicer.

Confocal microscopy has evolved to be a widely adopted imaging technique in molecular biology and is frequently utilized to achieve accurate subcellular localization of proteins. Applying colocalization analysis on image z-stacks obtained from confocal fluorescence microscopes is a dependable method of revealing the relationship between different molecules. In addition, despite the established advantages and growing adoption of 3D visualization software in various microscopy research domains, there have been few systems that can support colocalization analysis within a user-specified region of interest (ROI).

A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress.

DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs).

Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL.

Targeting the DNA damage response in hematological malignancies.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g.

Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis.

Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM.

Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma.

Unlabelled: Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets.

Super-enhancer-driven TOX2 mediates oncogenesis in Natural Killer/T Cell Lymphoma.

Background: Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies.

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.

Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition.

Excessive genomic instability coupled with abnormalities in DNA repair pathways induces high levels of 'replication stress' when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention towards targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1, and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective ATR kinase inhibitor elimusertib (BAY 1895344) has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking.

Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy.

Background: Immune checkpoint inhibitors (ICI) are now standard-of-care treatment for patients with metastatic gastric cancer (GC). To guide patient selection for ICI therapy, programmed death ligand-1 (PD-L1) biomarker expression is routinely assessed via immunohistochemistry (IHC). However, with an increasing number of approved ICIs, each paired with a different PD-L1 antibody IHC assay used in their respective landmark trials, there is an unmet clinical and logistical need for harmonization.

A bio-functional polymer that prevents retinal scarring through modulation of NRF2 signalling pathway.

One common cause of vision loss after retinal detachment surgery is the formation of proliferative and contractile fibrocellular membranes. This aberrant wound healing process is mediated by epithelial-mesenchymal transition (EMT) and hyper-proliferation of retinal pigment epithelial (RPE) cells. Current treatment relies primarily on surgical removal of these membranes.

p53-NEIL1 co-abnormalities induce genomic instability and promote synthetic lethality with Chk1 inhibition in multiple myeloma having concomitant 17p13(del) and 1q21(gain).

Recurrent cytogenetic abnormalities are the main hallmark of multiple myeloma (MM) and patients having 2 or more high-risk prognostic events are associated with extremely poor outcome. 17p13(del) and 1q21(gain) are critical and independent high-risk cytogenetic markers, however, the biological significance underlying the poor outcome in MM patients having co-occurrence of both these chromosomal aberrations has never been interrogated. Herein, we identified that patients harbouring concomitant 17p13(del) with 1q21(gain) demonstrated the worst prognosis as compared to patients with single- (either 17p13(del) or 1q21(gain)) and with no chromosomal events (WT for both chromosomal loci); and they are highly enriched for genomic instability (GI) signature.