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

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

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

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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.

Original language	English
Pages (from-to)	1906-1918.e8
Number of pages	21
Journal	Cell reports
Volume	26
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2019.01.050
Publication status	Published - 12-Feb-2019

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Jung, J., Buisman, S. C., Weersing, E., Dethmers-Ausema, A., Zwart, E., Schepers, H., Dekker, M. R., Lazare, S. S., Hammerl, F., Skokova, Y., Kooistra, S. M., Klauke, K., Poot, R. A., Bystrykh, L. V., & de Haan, G. (2019). CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions. Cell reports, 26(7), 1906-1918.e8. https://doi.org/10.1016/j.celrep.2019.01.050

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

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.",

author = "Johannes Jung and Buisman, {Sonja C} and Ellen Weersing and Albertina Dethmers-Ausema and Erik Zwart and Hein Schepers and Dekker, {Mike R} and Lazare, {Seka S} and Franziska Hammerl and Yulia Skokova and Kooistra, {Susanne M} and Karin Klauke and Poot, {Raymond A} and Bystrykh, {Leonid V} and {de Haan}, Gerald",

year = "2019",

month = feb,

day = "12",

doi = "10.1016/j.celrep.2019.01.050",

language = "English",

volume = "26",

pages = "1906--1918.e8",

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Jung, J, Buisman, SC, Weersing, E , Dethmers-Ausema, A , Zwart, E , Schepers, H, Dekker, MR, Lazare, SS, Hammerl, F, Skokova, Y, Kooistra, SM, Klauke, K, Poot, RA, Bystrykh, LV & de Haan, G 2019, 'CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions', Cell reports, vol. 26, no. 7, pp. 1906-1918.e8. https://doi.org/10.1016/j.celrep.2019.01.050

TY - JOUR

T1 - CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions

AU - Jung, Johannes

AU - Buisman, Sonja C

AU - Weersing, Ellen

AU - Dethmers-Ausema, Albertina

AU - Zwart, Erik

AU - Schepers, Hein

AU - Dekker, Mike R

AU - Lazare, Seka S

AU - Hammerl, Franziska

AU - Skokova, Yulia

AU - Kooistra, Susanne M

AU - Klauke, Karin

AU - Poot, Raymond A

AU - Bystrykh, Leonid V

AU - de Haan, Gerald

PY - 2019/2/12

Y1 - 2019/2/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2019.01.050

DO - 10.1016/j.celrep.2019.01.050

M3 - Article

C2 - 30759399

SN - 2211-1247

VL - 26

SP - 1906-1918.e8

JO - Cell reports

JF - Cell reports

IS - 7

ER -

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

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