248 A developmental cellular hierarchy in melanoma uncouples growth and metastatic phenotypes

AbstractDespite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two thirds of patients will relapse with fatal disease within 5 years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known of the genetic determinants of their stemness properties 6–8. Although much AML research focuses on mutational processes and their impact on gene expression programs, the genetic determinants of cell state properties including stemness expand beyond mutations, relying on the genetic architecture captured in the chromatin of each cell 9–11. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC), we identified genetic determinants of primitive populations enriched for LSCs and HSCs in comparison with their downstream mature progeny by investigating their chromatin accessibility. Our work reveals how distinct transposable element (TE) subfamilies are used in primitive versus mature populations, functioning as docking sites for stem cell-associated regulators of genome topology, including CTCF, or lineage-specific transcription regulators in primitive and mature populations, respectively. We further show how TE subfamilies accessible in LSCs define docking sites for several oncogenic drivers in AML, namely FLI1, LYL1 and MEIS1. Using chromatin accessibility profiles from a cohort of AML patients, we further show the clinical utility of our TE accessibility-based LSCTE121 scoring scheme to identify patients with high rates of relapse. Collectively, our work reveals how different accessible TE subfamilies serve as genetic determinants of stemness properties in normal and leukemic hematopoietic stem cells.

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A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR

Neuro-Oncology ◽

10.1093/neuonc/noy204 ◽

2018 ◽

Vol 21 (6) ◽

pp. 719-729 ◽

Cited By ~ 3

Author(s):

Talal F Al-Mayhani ◽

Richard M Heywood ◽

Vamsidhara Vemireddy ◽

Justin D Lathia ◽

Sara G M Piccirillo ◽

...

Keyword(s):

Growth Factor Receptor ◽

Hierarchical Organization ◽

Egfr Signaling ◽

Resistant Disease ◽

Egfr Expression ◽

Ng2 Cells ◽

Human Gbm ◽

Rna Knockdown ◽

Cellular Hierarchy ◽

Relationship Of

Abstract Background Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2− cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. Methods Single GBM NG2+ and NG2− cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2− cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. Results Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2− or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. Conclusions These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2− cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.

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A single-cell survey of cellular hierarchy in acute myeloid leukemia

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00941-y ◽

2020 ◽

Vol 13 (1) ◽

Cited By ~ 2

Author(s):

Junqing Wu ◽

Yanyu Xiao ◽

Jie Sun ◽

Huiyu Sun ◽

Haide Chen ◽

...

Keyword(s):

Single Cell ◽

Myeloid Leukemia ◽

Drug Targets ◽

Progenitor Cell ◽

Potential Drug ◽

Smrt Sequencing ◽

Cellular Hierarchy ◽

Potential Drug Targets ◽

Cancer Attractor ◽

Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate integrative analysis on the hierarchy of different AML subtypes. Methods Using Microwell-seq, a high-throughput single-cell mRNA sequencing platform, we analyzed the cellular hierarchy of bone marrow samples from 40 patients and 3 healthy donors. We also used single-cell single-molecule real-time (SMRT) sequencing to investigate the clonal heterogeneity of AML cells. Results From the integrative analysis of 191727 AML cells, we established a single-cell AML landscape and identified an AML progenitor cell cluster with novel AML markers. Patients with ribosomal protein high progenitor cells had a low remission rate. We deduced two types of AML with diverse clinical outcomes. We traced mitochondrial mutations in the AML landscape by combining Microwell-seq with SMRT sequencing. We propose the existence of a phenotypic “cancer attractor” that might help to define a common phenotype for AML progenitor cells. Finally, we explored the potential drug targets by making comparisons between the AML landscape and the Human Cell Landscape. Conclusions We identified a key AML progenitor cell cluster. A high ribosomal protein gene level indicates the poor prognosis. We deduced two types of AML and explored the potential drug targets. Our results suggest the existence of a cancer attractor.

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Decision letter: Coopted temporal patterning governs cellular hierarchy, heterogeneity and metabolism in Drosophila neuroblast tumors

10.7554/elife.50375.034 ◽

2019 ◽

Author(s):

Bart Deplancke

Keyword(s):

Temporal Patterning ◽

Cellular Hierarchy

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Abstract 475: Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells

10.1158/1538-7445.am2011-475 ◽

2011 ◽

Author(s):

Marc I. Damelin ◽

Kenneth G. Geles ◽

Maximillian T. Follettie ◽

Ping Yuan ◽

Michelle Baxter ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Initiating Cells ◽

Cellular Hierarchy

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Abstract 4204: The cellular hierarchy of intestinal tumors

10.1158/1538-7445.am2015-4204 ◽

2015 ◽

Author(s):

Ryoji Yao ◽

Tetsuo Noda

Keyword(s):

Intestinal Tumors ◽

Cellular Hierarchy

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Correction: Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq

Leukemia ◽

10.1038/s41375-021-01398-9 ◽

2021 ◽

Author(s):

Caner Saygin ◽

Eileen Hu ◽

Pu Zhang ◽

Steven Sher ◽

Arletta Lozanski ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Genomic Analysis ◽

Cellular Hierarchy ◽

Acute Myeloid

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Cellular hierarchy and molecular mechanisms underlying haematopoietic stem cell development

Experimental Hematology ◽

10.1016/j.exphem.2017.06.012 ◽

2017 ◽

Vol 53 ◽

pp. S25

Author(s):

Alexander Medvinsky ◽

Stanislav Rybtsov ◽

Alison McGarvey ◽

Celine Souilhol ◽

Antoniana Batsivari

Keyword(s):

Stem Cell ◽

Molecular Mechanisms ◽

Cell Development ◽

Haematopoietic Stem Cell ◽

Cellular Hierarchy

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Development of Hematopoietic and Endothelial Cells from Human Embryonic Stem Cells: Lessons from the Studies using Mouse as a Model

The Scientific World JOURNAL ◽

10.1100/tsw.2007.310 ◽

2007 ◽

Vol 7 ◽

pp. 1950-1964 ◽

Cited By ~ 2

Author(s):

Anna Jezierski ◽

Albert Swedani ◽

Lisheng Wang

Keyword(s):

Endothelial Cells ◽

Stem Cell ◽

Embryonic Stem Cell ◽

Cell Model ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cell ◽

Model System ◽

Stem Cell Model ◽

Cell Model System ◽

Cellular Hierarchy

The current progress using the human embryonic stem cell (hESC) model system has provided much insight into the early origins of the hematopoietic and endothelial lineages, particularly the elusive hemangioblast. Recently, the cellular hierarchy and molecular regulation controlling hematopoietic commitment have been further elucidated. These findings not only provide new insights into early human development, but also advance the knowledge required to develop techniques capable of generating a given cell type for potential clinical applications. This review will focus on the latest advances using the hESC model system, capitalizing on the well-established mouse embryonic stem cell model system, as a means to investigate the lineage commitment events underlying the early embryonic development of human hematopoietic and endothelial cells.

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