title: Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Jasper
authors.initials: J
authors.lastname: Mullenders
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aranda-Orgilles
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Priscillia
authors.initials: P
authors.lastname: Lhoumaud
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Matthew
authors.initials: M
authors.lastname: Keller
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Juhee
authors.initials: J
authors.lastname: Pae
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Kayembe
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Pedro P
authors.initials: PP
authors.lastname: Rocha
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Ramya
authors.initials: R
authors.lastname: Raviram
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Yixiao
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Mirimus Inc., Woodbury, NY 11797.
authors.forename: Prem K
authors.initials: PK
authors.lastname: Premsrirut
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
authors.forename: Luisa
authors.initials: L
authors.lastname: Cimmino
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hoehn
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Iannis.Aifantis@nyumc.org.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000328:Adult; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002843:Chromatin / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D009196:Myeloproliferative Disorders / Q000209:etiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D025521:Tumor Suppressor Proteins; D000097722:Cohesins