title: Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.
abstract: Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease.
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Mazumdar
authors.affiliation: Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Seethu
authors.initials: S
authors.lastname: Xavy
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reinisch
authors.affiliation: Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: M Ryan
authors.initials: MR
authors.lastname: Corces
authors.affiliation: Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Flynn
authors.affiliation: Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Buenrostro
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Chan
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Koenig
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Wan-Jen
authors.initials: WJ
authors.lastname: Hong
authors.affiliation: Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: rmajeti@stanford.edu.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D009154:Mutation; D013234:Stem Cells / Q000166:cytology*; D000071230:Transcriptional Regulator ERG / Q000378:metabolism; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D050676:Core Binding Factor Alpha 2 Subunit; D050989:GATA2 Transcription Factor; D000071230:Transcriptional Regulator ERG; D000097722:Cohesins; C072312:ERG protein, human; C494711:GATA2 protein, human; C493728:RUNX1 protein, human