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Cell Rep. 2019 Feb 12;26(7):1906-1918.e8. doi: 10.1016/j.celrep.2019.01.050.

CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions.

Author information

1
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
2
Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
3
Department of Cell Biology, ErasmusMC, Rotterdam, the Netherlands.
4
University Hospital of Tübingen, Tübingen, Germany.
5
Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
6
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: l.bystrykh@umcg.nl.
7
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: g.de.haan@umcg.nl.

Abstract

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.

KEYWORDS:

CBX7; Polycomb; SETDB1; hematopoietic stem cells; leukemia

PMID:
30759399
DOI:
10.1016/j.celrep.2019.01.050
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