CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions
Summary: In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftm...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719300683 |
| _version_ | 1819174179071590400 |
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| author | Johannes Jung Sonja C. Buisman Ellen Weersing Albertina Dethmers-Ausema Erik Zwart Hein Schepers Mike R. Dekker Seka S. Lazare Franziska Hammerl Yulia Skokova Susanne M. Kooistra Karin Klauke Raymond A. Poot Leonid V. Bystrykh Gerald de Haan |
| author_facet | Johannes Jung Sonja C. Buisman Ellen Weersing Albertina Dethmers-Ausema Erik Zwart Hein Schepers Mike R. Dekker Seka S. Lazare Franziska Hammerl Yulia Skokova Susanne M. Kooistra Karin Klauke Raymond A. Poot Leonid V. Bystrykh Gerald de Haan |
| author_sort | Johannes Jung |
| collection | DOAJ |
| description | Summary: In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in acute myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7-binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover non-canonical crosstalk between distinct pathways, revealing therapeutic opportunities for leukemia. : Hematopoietic stem cells ensure production of mature blood cells during the lifetime of an individual. Excessive self-renewal of stem cells leads to leukemia. Jung et at. identify a mechanism that controls self-renewal of normal and leukemic stem cells and show how pharmacological molecules that inhibit this pathway repress leukemic cell growth. Keywords: hematopoietic stem cells, leukemia, Polycomb, CBX7, SETDB1 |
| first_indexed | 2024-12-22T20:34:51Z |
| format | Article |
| id | doaj.art-8e9f30d38fc142b58e0349be1f6e3dd2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T20:34:51Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-8e9f30d38fc142b58e0349be1f6e3dd22022-12-21T18:13:28ZengElsevierCell Reports2211-12472019-02-0126719061918.e8CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical InteractionsJohannes Jung0Sonja C. Buisman1Ellen Weersing2Albertina Dethmers-Ausema3Erik Zwart4Hein Schepers5Mike R. Dekker6Seka S. Lazare7Franziska Hammerl8Yulia Skokova9Susanne M. Kooistra10Karin Klauke11Raymond A. Poot12Leonid V. Bystrykh13Gerald de Haan14European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsDepartment of Cell Biology, ErasmusMC, Rotterdam, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsUniversity Hospital of Tübingen, Tübingen, GermanyDepartment of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsDepartment of Cell Biology, ErasmusMC, Rotterdam, the NetherlandsEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Corresponding authorEuropean Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Corresponding authorSummary: In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in acute myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7-binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover non-canonical crosstalk between distinct pathways, revealing therapeutic opportunities for leukemia. : Hematopoietic stem cells ensure production of mature blood cells during the lifetime of an individual. Excessive self-renewal of stem cells leads to leukemia. Jung et at. identify a mechanism that controls self-renewal of normal and leukemic stem cells and show how pharmacological molecules that inhibit this pathway repress leukemic cell growth. Keywords: hematopoietic stem cells, leukemia, Polycomb, CBX7, SETDB1http://www.sciencedirect.com/science/article/pii/S2211124719300683 |
| spellingShingle | Johannes Jung Sonja C. Buisman Ellen Weersing Albertina Dethmers-Ausema Erik Zwart Hein Schepers Mike R. Dekker Seka S. Lazare Franziska Hammerl Yulia Skokova Susanne M. Kooistra Karin Klauke Raymond A. Poot Leonid V. Bystrykh Gerald de Haan CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions Cell Reports |
| title | CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions |
| title_full | CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions |
| title_fullStr | CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions |
| title_full_unstemmed | CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions |
| title_short | CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions |
| title_sort | cbx7 induces self renewal of human normal and malignant hematopoietic stem and progenitor cells by canonical and non canonical interactions |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719300683 |
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