Investigating the Role of TP53 in Peripheral T-Cell Lymphoma-GATA3 Subtype

Introduction: Non-Hodgkin Lymphoma (NHL) accounts for 4.1% of all cancers in the United States. Peripheral T-Cell Lymphoma (PTCL) consists of ~10-15% of all NHL in the Western world. 30-50% of these PTCLs are not classifiable/diagnosed and are instead designated as PTCL-Not Otherwise Specified (PTCL-NOS). The two major molecular subgroups within PTCL-NOS are PTCL-TBX21 and PTCL-GATA3, determined by their distinct T-helper (TH) transcriptional programs. GATA3 and TBX21 are the master-transcriptional regulators of TH2- and TH1-cell differentiation, respectively. The overall survival analysis of PTCL-NOS cases illustrates the clinical outcome of PTCL-GATA3 cases are significantly lower than PTCL-TBX21 cases over a broad timeframe. Thus, the need for understanding the underlying mechanism and finding therapeutic targets is at the utmost importance. Background: TP53 mutations and/or TP53 loss deletions are frequent in PTCL-GATA3 cases, compared to PTCL-TBX21. TP53 is a protein that is essential in cycle regulation but also acts as a tumor suppressor. It stops cells from dividing if they have mutated or damaged DNA. Due to the high mutation rates observed in this subtype, we believe TP53 could play a major role in this mechanism. Therefore, it was important to focus on the TP53-GATA3 interaction at the genomic level. Prior studies using chromatin immunoprecipitation (ChIP)-qPCR on the intron 3 full GATA3 region suggested there was more TP53 binding in this intron region compared to other regions. Therefore, we designed a research strategy to determine the specific binding regions of TP53-GATA3 interaction and the function of the TP53 binding.https://digitalcommons.unmc.edu/surp2023/1003/thumbnail.jp

Subtype-Specific and Co-Occurring Genetic Alterations in B-cell Non-Hodgkin Lymphoma

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis

Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.

Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity

Eutrophication of US Freshwaters: Analysis of Potential Economic Damages

Human-induced eutrophication degrades freshwater systems worldwide by reducing water quality and altering ecosystem structure and function. We compared current total nitrogen (TN) and phosphorus (TP) concentrations for the U.S. Environmental Protection Agency nutrient ecoregions with estimated reference conditions. In all nutrient ecoregions, current median TN and TP values for rivers and lakes exceeded reference median values. In 12 of 14 ecoregions, over 90% of rivers currently exceed reference median values. We calculated potential annual value losses in recreational water usage, waterfront real estate, spending on recovery of threatened and endangered species, and drinking water. The combined costs were approximately $2.2 billion annually as a result of eutrophication in U.S. freshwaters. The greatest economic losses were attributed to lakefront property values ($0.3?2.8 billion per year, although this number was poorly constrained) and recreational use ($0.37?1.16 billion per year). Our evaluation likely underestimates economic losses incurred from freshwater eutrophication. We document potential costs to identify where restoring natural nutrient regimes can have the greatest economic benefits. Our research exposes gaps in current records (e.g., accounting for frequency of algal blooms and fish kills) and suggests further research is necessary to refine cost estimates

Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma

Purpose: To Identify tumor suppressor genes epigenetically silenced by promoter hypermethylation in extranodal natural killer cell lymphoma (NKCL)