Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome

Yang, Chao; Siebert, Jason R.; Burns, Robert T.; Gerbec, Zachary J.; Bonacci, Benedetta; Rymaszewski, Amy L.; Rau, Mary; Riese, Matthew J.; Rao, Sridhar; Carlson, Karen-Sue; Routes, John M.; Verbsky, James; Thakar, Monica S.; Malarkannan, Subramaniam

doi:10.1038/s41467-019-11947-7

Cited by 226 publications

(266 citation statements)

References 77 publications

(101 reference statements)

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“…However, transcriptomic profiles of NK cells are beginning to demonstrate a wide range of heterogeneity within NK cell populations. For example, one study utilized single cell RNA sequencing (scRNA seq) to determine transitional populations of NK cells within bone marrow and PB that exist between these two examples (269). Another group demonstrated that NK cells exhibit organ-specific transcriptional profiles (270).…”

Section: Omics Studies On Nk Cell Activationmentioning

confidence: 99%

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Murin

2020

Front. Immunol.

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It has been well-established that antibody isotype, glycosylation, and epitope all play roles in the process of antibody dependent cellular cytotoxicity (ADCC). For natural killer (NK) cells, these phenotypes are linked to cellular activation through interaction with the IgG receptor FcγRIIIa, a single pass transmembrane receptor that participates in cytoplasmic signaling complexes. Therefore, it has been hypothesized that there may be underlying spatial and geometric principles that guide proper assembly of an activation complex within the NK cell immune synapse. Further, synergy of antibody phenotypic properties as well as allosteric changes upon antigen binding may also play an as-of-yet unknown role in ADCC. Understanding these facets, however, remains hampered by difficulties associated with studying immune synapse dynamics using classical approaches. In this review, I will discuss relevant NK cell biology related to ADCC, including the structural biology of Fc gamma receptors, and how the dynamics of the NK cell immune synapse are being studied using innovative microscopy techniques. I will provide examples from the literature demonstrating the effects of spatial and geometric constraints on the T cell receptor complex and how this relates to intracellular signaling and the molecular nature of lymphocyte activation complexes, including those of NK cells. Finally, I will examine how the integration of high-throughput and "omics" technologies will influence basic NK cell biology research moving forward. Overall, the goal of this review is to lay a basis for understanding the development of drugs and therapeutic antibodies aimed at augmenting appropriate NK cell ADCC activity in patients being treated for a wide range of illnesses.

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Section: Omics Studies On Nk Cell Activationmentioning

confidence: 99%

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Murin

2020

Front. Immunol.

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“…Specifically, ALL NK cells mainly represented clusters 10 and 16 that matched granzyme K (GZMK) expressing immature CD56 bright and translational NK cells (gene set scores in Fig. 4e represent the NK subtypes from a scRNA-seq study [45]). In comparison, the majority of the normal BM NK cells represented the mature or terminal NK cells (cluster 0) that express granzyme B (GZMB) and perforin (PRF1).…”

Section: The E/r+ Bm Immune Microenvironment Has Low Abundance and Acmentioning

confidence: 99%

“…Top 5 genes per cluster based on test score were extracted. Scores for NK subtype gene sets from [45] were calculated with the score_genes-function using the top 20 genes per gene set sorted by log-fold change.…”

Section: Nk Cell Analysismentioning

confidence: 99%

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

Mehtonen

Teppo

Lahnalampi

et al. 2020

Preprint

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Tight regulatory loops orchestrate commitment to B-cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention.We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion.We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment-resistance, we show that selective inhibitors of ETS-transcription factors could effectively reduce cell viability.Our data provide a detailed picture of the transcription factor activities that characterize both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.

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“…We used the overlapping test implemented in the GeneOverlap R package (https://github.com/shenlab-sinai/geneoverlap) to assess the overlap of our NHP NK cell signature with published collections of gene sets and pathways (Chaussabel et al, 2008;Liberzon et al, 2011;Nakaya et al, 2011;Newman et al, 2015;Costanzo et al, 2018;Yang et al, 2019). All gene sets and pathways that were enriched with a false discovery (FDR) q value cut-off of 0.05 were selected and the overlapping genes between these significant signatures and our NK RMtsig were used to generate heatmaps and gene networks.…”

Section: Pathways Enrichment Analysesmentioning

confidence: 99%

Delineation and Modulation of the Natural Killer Cell Transcriptome in Rhesus Macaques During ZIKV and SIV Infections

Aïd

Ram

Bosinger³

et al. 2020

Front. Cell. Infect. Microbiol.

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Natural killer (NK) cells are crucial regulators of antiviral and anti-tumor immune responses. Although in humans some NK cell transcriptional programs are relatively well-established, NK cell transcriptional networks in non-human primates (NHP) remain poorly delineated. Here we performed RNA-Seq experiments using purified NK cells from experimentally naïve rhesus macaques, providing the first transcriptional characterization of pure NK cells in any NHP species. This novel NK cell transcriptomic signature (NK RMtsig) overlaps with published human NK signatures, allowing us to identify new key signaling and transcription factor networks underlying NK cell function. Finally, we show that applying NK RMtsig to an unrelated rhesus macaque cohort infected with SIVmac251 or ZIKV can sensitively detect NK cell repertoire perturbations, thus confirming applicability of this approach. In sum, we propose this NHP NK cell signature will serve as a useful resource for future studies involving infection, disease or treatment modalities in NHP.

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Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome

Cited by 226 publications

References 77 publications

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

Delineation and Modulation of the Natural Killer Cell Transcriptome in Rhesus Macaques During ZIKV and SIV Infections

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