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

• Published in: Cell reports (Cambridge) Vol. 26; no. 7; pp. 1906 - 1918.e8
• Main Authors: Jung, Johannes, Buisman, Sonja C., Weersing, Ellen, Dethmers-Ausema, Albertina, Zwart, Erik, Schepers, Hein, Dekker, Mike R., Lazare, Seka S., Hammerl, Franziska, Skokova, Yulia, Kooistra, Susanne M., Klauke, Karin, Poot, Raymond A., Bystrykh, Leonid V., de Haan, Gerald
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2019; Elsevier
• Subjects: Animals; CBX7; Female; Fetal Blood - cytology; Fetal Blood - metabolism; HEK293 Cells; hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Heterografts; Histone-Lysine N-Methyltransferase - metabolism; HL-60 Cells; Humans; K562 Cells; leukemia; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Polycomb; Polycomb Repressive Complex 1 - biosynthesis; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; SETDB1; Stem Cells - cytology; Stem Cells - metabolism; Transcription, Genetic; leukemia; CBX7; Polycomb; SETDB1; hematopoietic stem cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.01.050

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. [Display omitted] •CBX7 regulates self-renewal of human primitive normal and leukemic cells•CBX7 binds SETDB1 and its inhibition induces differentiation of AML 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.