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Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.
Mazumdar, Claire; Shen, Ying; Xavy, Seethu; Zhao, Feifei; Reinisch, Andreas; Li, Rui; Corces, M Ryan; Flynn, Ryan A; Buenrostro, Jason D; Chan, Steven M; Thomas, Daniel; Koenig, Julie L; Hong, Wan-Jen; Chang, Howard Y; Majeti, Ravindra.
Afiliación
  • Mazumdar C; 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.
  • Shen Y; Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Xavy S; 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.
  • Zhao F; 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.
  • Reinisch A; 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.
  • Li R; Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Corces MR; 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.
  • Flynn RA; Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Buenrostro JD; 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.
  • Chan SM; 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.
  • Thomas D; 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.
  • Koenig JL; 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.
  • Hong WJ; 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.
  • Chang HY; Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Majeti R; 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.
Cell Stem Cell ; 17(6): 675-688, 2015 Dec 03.
Article en En | MEDLINE | ID: mdl-26607380
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre / Células Madre Hematopoyéticas / Proteínas Cromosómicas no Histona / Proteínas de Ciclo Celular / Mutación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Stem Cell Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre / Células Madre Hematopoyéticas / Proteínas Cromosómicas no Histona / Proteínas de Ciclo Celular / Mutación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Stem Cell Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos