High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti‐CD74‐drug conjugate

Background: Aging is a pleiotropic process affecting many aspects of organismal and cellular 1 physiology. Mammalian organisms are composed of a constellation of distinct cell type and state 2 identities residing within different tissue environments. Due to technological limitations, the study 3 of aging has traditionally focused on changes within individual cell types, or the aggregate changes 4 across cell types within a tissue. The influence of cell identity and tissue environment on the trajectory 5 of aging therefore remains unclear.6Results: Here, we perform single cell RNA-seq on >50,000 individual cells across three tissues in 7 young and aged mice. These molecular profiles allow for comparison of aging phenotypes across cell 8 types and tissue environments. We find transcriptional features of aging common across many cell 9 types, as well as features of aging unique to each type. Leveraging matrix factorization and optimal 10 transport methods, we compute a trajectory and magnitude of aging for each cell type. We find that 11 cell type exerts a larger influence on these measures than tissue environment. 12Conclusion: In this study, we use single cell RNA-seq to dissect the influence of cell identity and 13 tissue environment on the aging process. Single cell analysis reveals that cell identities age in unique 14 ways, with some common features of aging shared across identities. We find that both cell identities 15 and tissue environments exert influence on the trajectory and magnitude of aging, with cell identity 16 influence predominating. These results suggest that aging manifests with unique directionality and 17 magnitude across the diverse cell identities in mammals. 18 Introduction 19Aging is a gradual process of functional and homeostatic decline in living systems. This decline results in increased 20 mortality risk and disease prevalence, eventually resulting in death. Aging appears to be a conserved feature of 21 eukaryotic biology, affecting organisms as phylogenetically diverse as the single celled S. cerevisiea, the eutelic 22 nematode C. elegans, mice, and humans [45, 63, 91]. Despite the near universal nature of the aging process, the 23 underlying causes of aging are poorly understood. Aging phenotypes have been observed and hypotheses have been 24 proposed for more than a hundred years [97, 50, 37, 64], but we do not yet know the cellular and molecular players 25 that cause aging or how they differ between biological contexts. Both the fundamental nature of aging and its negative 26 effects provide motivation to enumerate these players and establish causal relationships among aging phenotypes. 27Mammalian aging phenotypes manifest at the organismal, tissue, cellular, and molecular levels [100]. Extensive 28 research has produced catalogs of aging phenotypes at the physiological level, providing functional and behavioral 29 * Equal Contribution † Current Address: DuPont Nutrition and Biosciences, 200 Powder Mill Rd, Wilmington, DE, 19803 PREPRINT hallmarks of age related decline. Likewi...

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“…4F; q < 0.05, Wilcoxon Rank Sums test). Each of these genes has previously been associated with neoplasia [102, 49, 60].…”

Section: Resultsmentioning

confidence: 99%

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

Kimmel

Penland

Rubinstein

et al. 2019

Preprint

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“…For example, CD74 is widely expressed in human immune cells, including B cells, activated T cell subsets, DATABASE ANALYSIS monocytes, macrophages, and dendritic cells [27]. Although CD74 was originally identified as an MHC class II chaperone, accumulating evidence shows that CD74 has diverse roles in immune responses [28]. Given CD74 as a hub gene in our study, we hypothesized that the interplay between SETDB1 and CD74 has a crucial role in immune responses and thus regulates the development of BC.…”

Section: Discussionmentioning

confidence: 99%

High SET Domain Bifurcated 1 (SETDB1) Expression Predicts Poor Prognosis in Breast Carcinoma

Zhou

Tang

et al. 2020

Med Sci Monit

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Departmental sources Background: SETDB1, an H3K9-specific histone methyltransferase, plays important roles in the progression of various human cancers. However, the expression patterns and its clinical roles of SETDB1 remain elusive in breast cancer (BC). Material/Methods: The transcriptional level of SETDB1 and survival data in BC were analyzed through UALCAN, ONCOMINE, and Pan Cancer Prognostics Database. SETDB1 protein expression was assessed by immunohistochemistry (IHC) in 159 BC tissue samples. The associations between SETDB1 expression and clinical pathological characteristics of patients were analyzed. The GEO dataset GSE108656 was downloaded and analyzed to identify the differentially expressed genes (DEGs) between control and BC cells targeting interference with SETDB. The DEGs were further integrated by bioinformatics analysis to decipher the key signaling pathways and hub genes that are regulated by SETDB. Results: The public databases showed the level of SETDB1 mRNA was significantly upregulated in BC. Our IHC results demonstrated the level of SETDB1 protein was associated with tumor size (P=0.028), histopathological grading (P=0.012), lymph node metastasis (P<0.001), and TNM stage (P<0.001). High expression of SETDB1 indicated worse overall survival (P=0.015) and shorter relapse-free survival (P=0.027). The bioinformatic analysis of GSE108656 suggested that the SETDB1-related DEGs was mainly enriched in antigen processing and presentation, as well as immune networks in BC. The cytoHubba analysis suggested the top 10 hub genes were IL6,

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“…4F). Each of these genes has previously been associated with neoplasia (Kinsey et al 2014;Li et al 2017;Zhao et al 2019). We believe these cell states may therefore represent a lymphoma or prelymphoma, although exact diagnosis is difficult because of the histopathological definition of neoplastic malignancies.…”

Section: Aging Manifests Novel B Cell States In the Spleenmentioning

confidence: 96%

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

et al. 2019

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Aging is a pleiotropic process affecting many aspects of mammalian physiology. Mammals are composed of distinct cell type identities and tissue environments, but the influence of these cell identities and environments on the trajectory of aging in individual cells remains unclear. Here, we performed single-cell RNA-seq on >50,000 individual cells across three tissues in young and old mice to allow for direct comparison of aging phenotypes across cell types. We found transcriptional features of aging common across many cell types, as well as features of aging unique to each type. Leveraging matrix factorization and optimal transport methods, we found that both cell identities and tissue environments exert influence on the trajectory and magnitude of aging, with cell identity influence predominating. These results suggest that aging manifests with unique directionality and magnitude across the diverse cell identities in mammals. 2

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High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti‐CD74‐drug conjugate

Cited by 24 publications

References 43 publications

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

High SET Domain Bifurcated 1 (SETDB1) Expression Predicts Poor Prognosis in Breast Carcinoma

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

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