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

Johannes Jung | Zendy; Sonja Buisman | Zendy; Ellen Weersing | Zendy; Albertina Dethmers-Ausema | Zendy; Erik Zwart | Zendy; Hein Schepers | Zendy; Mike R. Dekker | Zendy; Seka Lazare | Zendy; Franziska Hammerl | Zendy; Yulia Skokova | Zendy; Susanne M. Kooistra | Zendy; Karin Klauke | Zendy; Raymond A. Poot | Zendy; Leonid Bystrykh | Zendy; Gerald de Haan | Zendy

Open Access

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

Author(s) -

Johannes Jung,

Sonja Buisman,

Ellen Weersing,

Albertina Dethmers-Ausema,

Erik Zwart,

Hein Schepers,

Mike R. Dekker,

Seka Lazare,

Franziska Hammerl,

Yulia Skokova,

Susanne M. Kooistra,

Karin Klauke,

Raymond A. Poot,

Leonid Bystrykh,

Gerald de Haan

Publication year - 2019

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2019.01.050

Subject(s) - chromatin , biology , haematopoiesis , microbiology and biotechnology , stem cell , histone , bmi1 , progenitor cell , cancer research , transcriptome , genetics , gene , gene expression

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.

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