title: Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis.
abstract: Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function.
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Viny
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ott
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Barbara
authors.initials: B
authors.lastname: Spitzer
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Martin
authors.initials: M
authors.lastname: Rivas
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Cem
authors.initials: C
authors.lastname: Meydan
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Efthymia
authors.initials: E
authors.lastname: Papalexi
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Department of Medicine, Rabin Medical Center, Beilinson Campus, Petah Tikvah 49100, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Yelin
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Shank
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Jaime
authors.initials: J
authors.lastname: Reyes
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: April
authors.initials: A
authors.lastname: Chiu
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Romin
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Boyko
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Swapna
authors.initials: S
authors.lastname: Thota
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 Department of Medicine, Harvard Medical School, Boston, MA 02115 leviner@mskcc.org james_bradner@dfci.harvard.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 leviner@mskcc.org james_bradner@dfci.harvard.edu.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D002843:Chromatin / Q000737:chemistry; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D057895:Haploinsufficiency; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics; D051379:Mice; D050799:STAT5 Transcription Factor / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D050799:STAT5 Transcription Factor; D051941:fms-Like Tyrosine Kinase 3; D000097722:Cohesins; C492317:SMC3 protein, mouse; C497971:Flt3 protein, mouse