CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions
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
Affiliations
Johannes Jung
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Sonja C. Buisman
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Ellen Weersing
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Albertina Dethmers-Ausema
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Erik Zwart
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Hein Schepers
Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Mike R. Dekker
Department of Cell Biology, ErasmusMC, Rotterdam, the Netherlands
Seka S. Lazare
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Franziska Hammerl
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Yulia Skokova
University Hospital of Tübingen, Tübingen, Germany
Susanne M. Kooistra
Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Karin Klauke
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Raymond A. Poot
Department of Cell Biology, ErasmusMC, Rotterdam, the Netherlands
Leonid V. Bystrykh
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Corresponding author
Gerald de Haan
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Corresponding author
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
