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 PMID:26438359  

Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms.

Jasper Mullenders | Beatriz Aranda-Orgilles | Priscillia Lhoumaud | Matthew Keller | Juhee Pae | Kun Wang | Clarisse Kayembe | Pedro P Rocha | Ramya Raviram | Yixiao Gong | Prem K Premsrirut | Aristotelis Tsirigos | Richard Bonneau | Jane A Skok | Luisa Cimmino | Daniela Hoehn | Iannis Aifantis
The Journal of experimental medicine | 2015

The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy.

Pubmed ID: 26438359

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: 1R01CA169784
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR001445
  • Agency: NCI NIH HHS, United States
    Id: R01 CA173636
  • Agency: NCI NIH HHS, United States
    Id: P30 CA016087
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM112192
  • Agency: NCI NIH HHS, United States
    Id: R01 CA133379
  • Agency: NCI NIH HHS, United States
    Id: R01 CA194923
  • Agency: NCI NIH HHS, United States
    Id: R01 CA149655
  • Agency: NCI NIH HHS, United States
    Id: R01 CA105129
  • Agency: NCI NIH HHS, United States
    Id: 5R01CA173636
  • Agency: NCI NIH HHS, United States
    Id: 1R01CA133379
  • Agency: NCI NIH HHS, United States
    Id: 1R01CA149655
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR00038
  • Agency: NCI NIH HHS, United States
    Id: R01 CA169784
  • Agency: NCI NIH HHS, United States
    Id: 5R01CA194923
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM086852
  • Agency: NCI NIH HHS, United States
    Id: 1R01CA105129
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR000038
  • Agency: NCI NIH HHS, United States
    Id: P30CA016087

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This is a list of tools and resources that we have found mentioned in this publication.


TM4 Microarray Software Suite - TIGR MultiExperiment Viewer (tool)

RRID:SCR_001915

A desktop application for the analysis, visualization and data-mining of large-scale genomic data. It is a versatile microarray tool, incorporating sophisticated algorithms for clustering, visualization, classification, statistical analysis and biological theme discovery. MeV generates informative and interrelated displays of expression and annotation data from single or multiple experiments. A huge array of alrogithms are included in MeV modules, and are available at a button-click, such as K-means clustering, Hierarchical clustering, t-Tests, Significance Analysis of Microarrays, Gene Set Enrichment Analysis, and EASE. Extensive documentation is available for helping new users get started with MeV. A Quickstart Guide provides the tutorial a brand new person will need to get their first dataset loaded and displayed in the program. Returning MEV users will want to check out the release notes to see what new features are available in the latest versions of the program. Tutorials have been written about several of its more involved features.

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BioLegend (tool)

RRID:SCR_001134

Commercial antibody supplier and developer for biomedical research. These products are compatible with use in flow cytometry and mass cytometry, immunoprecipitation and chip, western blotting, immunofluorescence microscopy, and quantitative multiplexing.

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A statistical framework for genomic data fusion (tool)

RRID:SCR_007219

A statistical framework for genomic data fusion is a computational framework for integrating and drawing inferences from a collection of genome-wide measurements. Each dataset is represented via a kernel function, which defines generalized similarity relationships between pairs of entities, such as genes or proteins. The kernel representation is both flexible and efficient, and can be applied to many different types of data. Furthermore, kernel functions derived from different types of data can be combined in a straightforward fashion. Recent advances in the theory of kernel methods have provided efficient algorithms to perform such combinations in a way that minimizes a statistical loss function. These methods exploit semidefinite programming techniques to reduce the problem of finding optimizing kernel combinations to a convex optimization problem. Computational experiments performed using yeast genome-wide datasets, including amino acid sequences, hydropathy profiles, gene expression data and known protein-protein interactions, demonstrate the utility of this approach. A statistical learning algorithm trained from all of these data to recognize particular classes of proteins--membrane proteins and ribosomal proteins--performs significantly better than the same algorithm trained on any single type of data. Matlab code to center a kernel matrix and Matlab code for normalization are available.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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Cuffdiff (tool)

RRID:SCR_001647

Software that estimates expression at transcript-level resolution and controls for variability evident across replicate libraries.

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PeaKDEck (tool)

RRID:SCR_004268

A peak-calling software program for DNAseI-seq data.

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HTSeq (tool)

RRID:SCR_005514

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on February 28,2023. Software Python package that provides infrastructure to process data from high-throughput sequencing assays. While the main purpose of HTSeq is to allow you to write your own analysis scripts, customized to your needs, there are also a couple of stand-alone scripts for common tasks that can be used without any Python knowledge.

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TopHat (tool)

RRID:SCR_013035

Software tool for fast and high throughput alignment of shotgun cDNA sequencing reads generated by transcriptomics technologies. Fast splice junction mapper for RNA-Seq reads. Aligns RNA-Seq reads to mammalian-sized genomes using ultra high-throughput short read aligner Bowtie, and then analyzes mapping results to identify splice junctions between exons.TopHat2 is accurate alignment of transcriptomes in presence of insertions, deletions and gene fusions.

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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Arcturus Cellect Laser Capture Microdissection System (tool)

RRID:SCR_018641

Laser capture microdissection system that includes infrared lasers. It can be used for laser capture microdissection LCM, ultraviolet UV laser cutting, sanger sequencing, next generation sequencing, and quantitative PCR.

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HEK293T (tool)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

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