A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis

Andrew Volk; Kaiwei Liang; Praveen Suraneni; Xinyu Li; Jianyun Zhao; Marinka Bulic; Stacy Marshall; Kirthi Pulakanti; Sebastien Malinge; Jeffrey Taub; Yubin Ge; Sridhar Rao; Elizabeth Bartom; Ali Shilatifard; John D. Crispino

doi:10.1016/j.ccell.2018.10.004

A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis

Andrew Volk, Kaiwei Liang, Praveen Suraneni, Xinyu Li, Jianyun Zhao, Marinka Bulic, Stacy Marshall, Kirthi Pulakanti, Sebastien Malinge, Jeffrey Taub, Yubin Ge, Sridhar Rao, Elizabeth Bartom, Ali Shilatifard, John D. Crispino^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of histones H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele is sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis. Volk et al. show that overexpression of the chromatin assembly factor complex subunit CHAF1B promotes leukemogenesis by interfering with chromatin occupancy of transcription factors that promote myeloid differentiation. Reducing CHAF1B activity suppresses leukemogenesis without impairing normal hematopoiesis.

Original language	English (US)
Pages (from-to)	707-723.e7
Journal	Cancer cell
Volume	34
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2018.10.004
State	Published - Nov 12 2018

Funding

The authors thank Gina Kirsammer and Christian Marinaccio for advice, and Peter Adams and Jiwang Zhang for providing critical reagents. The authors also would like to thank Guy Savageau for the Leucegene data and consultation regarding the expression of CHAF1A and CHAF1B. This study was supported by the Samuel Waxman Cancer Research Foundation (to J.D.C.) and the NIH (R01 CA101774 to J.D.C.; T32 CA080621 to A.V.). A.V. is supported by a Scholar Award from American Society of Hematology. Leukemia studies in the Shilatifard laboratory are supported by NCI R35 CA197569. E.B. is supported by R50 CA221848. This research was also supported by the Lurie Cancer Center. This work was supported by the Northwestern University Pathology Core and Flow Cytometry Facilities, funded by CCSG NCI CA060553, and cell sorting was performed on a BD FACSAria SORP system purchased with the support of NIH 1S10OD011996-01. The authors thank Gina Kirsammer and Christian Marinaccio for advice, and Peter Adams and Jiwang Zhang for providing critical reagents. The authors also would like to thank Guy Savageau for the Leucegene data and consultation regarding the expression of CHAF1A and CHAF1B. This study was supported by the Samuel Waxman Cancer Research Foundation (to J.D.C.) and the NIH ( R01 CA101774 to J.D.C.; T32 CA080621 to A.V.). A.V. is supported by a Scholar Award from American Society of Hematology. Leukemia studies in the Shilatifard laboratory are supported by NCI R35 CA197569 . E.B. is supported by R50 CA221848 . This research was also supported by the Lurie Cancer Center . This work was supported by the Northwestern University Pathology Core and Flow Cytometry Facilities, funded by CCSG NCI CA060553 , and cell sorting was performed on a BD FACSAria SORP system purchased with the support of NIH 1S10OD011996-01 .

Keywords

CAF1
CHAF1B
MLL-AF9
hematopoiesis

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2018.10.004

Cite this

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title = "A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis",

abstract = "CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of histones H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele is sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis. Volk et al. show that overexpression of the chromatin assembly factor complex subunit CHAF1B promotes leukemogenesis by interfering with chromatin occupancy of transcription factors that promote myeloid differentiation. Reducing CHAF1B activity suppresses leukemogenesis without impairing normal hematopoiesis.",

keywords = "CAF1, CHAF1B, MLL-AF9, hematopoiesis",

author = "Andrew Volk and Kaiwei Liang and Praveen Suraneni and Xinyu Li and Jianyun Zhao and Marinka Bulic and Stacy Marshall and Kirthi Pulakanti and Sebastien Malinge and Jeffrey Taub and Yubin Ge and Sridhar Rao and Elizabeth Bartom and Ali Shilatifard and Crispino, {John D.}",

note = "Funding Information: The authors thank Gina Kirsammer and Christian Marinaccio for advice, and Peter Adams and Jiwang Zhang for providing critical reagents. The authors also would like to thank Guy Savageau for the Leucegene data and consultation regarding the expression of CHAF1A and CHAF1B. This study was supported by the Samuel Waxman Cancer Research Foundation (to J.D.C.) and the NIH (R01 CA101774 to J.D.C.; T32 CA080621 to A.V.). A.V. is supported by a Scholar Award from American Society of Hematology. Leukemia studies in the Shilatifard laboratory are supported by NCI R35 CA197569. E.B. is supported by R50 CA221848. This research was also supported by the Lurie Cancer Center. This work was supported by the Northwestern University Pathology Core and Flow Cytometry Facilities, funded by CCSG NCI CA060553, and cell sorting was performed on a BD FACSAria SORP system purchased with the support of NIH 1S10OD011996-01. Funding Information: The authors thank Gina Kirsammer and Christian Marinaccio for advice, and Peter Adams and Jiwang Zhang for providing critical reagents. The authors also would like to thank Guy Savageau for the Leucegene data and consultation regarding the expression of CHAF1A and CHAF1B. This study was supported by the Samuel Waxman Cancer Research Foundation (to J.D.C.) and the NIH ( R01 CA101774 to J.D.C.; T32 CA080621 to A.V.). A.V. is supported by a Scholar Award from American Society of Hematology. Leukemia studies in the Shilatifard laboratory are supported by NCI R35 CA197569 . E.B. is supported by R50 CA221848 . This research was also supported by the Lurie Cancer Center . This work was supported by the Northwestern University Pathology Core and Flow Cytometry Facilities, funded by CCSG NCI CA060553 , and cell sorting was performed on a BD FACSAria SORP system purchased with the support of NIH 1S10OD011996-01 . Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.ccell.2018.10.004",

language = "English (US)",

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AU - Volk, Andrew

AU - Liang, Kaiwei

AU - Suraneni, Praveen

AU - Li, Xinyu

AU - Zhao, Jianyun

AU - Bulic, Marinka

AU - Marshall, Stacy

AU - Pulakanti, Kirthi

AU - Malinge, Sebastien

AU - Taub, Jeffrey

AU - Ge, Yubin

AU - Rao, Sridhar

AU - Bartom, Elizabeth

AU - Shilatifard, Ali

AU - Crispino, John D.

N1 - Funding Information: The authors thank Gina Kirsammer and Christian Marinaccio for advice, and Peter Adams and Jiwang Zhang for providing critical reagents. The authors also would like to thank Guy Savageau for the Leucegene data and consultation regarding the expression of CHAF1A and CHAF1B. This study was supported by the Samuel Waxman Cancer Research Foundation (to J.D.C.) and the NIH (R01 CA101774 to J.D.C.; T32 CA080621 to A.V.). A.V. is supported by a Scholar Award from American Society of Hematology. Leukemia studies in the Shilatifard laboratory are supported by NCI R35 CA197569. E.B. is supported by R50 CA221848. This research was also supported by the Lurie Cancer Center. This work was supported by the Northwestern University Pathology Core and Flow Cytometry Facilities, funded by CCSG NCI CA060553, and cell sorting was performed on a BD FACSAria SORP system purchased with the support of NIH 1S10OD011996-01. Funding Information: The authors thank Gina Kirsammer and Christian Marinaccio for advice, and Peter Adams and Jiwang Zhang for providing critical reagents. The authors also would like to thank Guy Savageau for the Leucegene data and consultation regarding the expression of CHAF1A and CHAF1B. This study was supported by the Samuel Waxman Cancer Research Foundation (to J.D.C.) and the NIH ( R01 CA101774 to J.D.C.; T32 CA080621 to A.V.). A.V. is supported by a Scholar Award from American Society of Hematology. Leukemia studies in the Shilatifard laboratory are supported by NCI R35 CA197569 . E.B. is supported by R50 CA221848 . This research was also supported by the Lurie Cancer Center . This work was supported by the Northwestern University Pathology Core and Flow Cytometry Facilities, funded by CCSG NCI CA060553 , and cell sorting was performed on a BD FACSAria SORP system purchased with the support of NIH 1S10OD011996-01 . Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/11/12

Y1 - 2018/11/12

N2 - CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of histones H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele is sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis. Volk et al. show that overexpression of the chromatin assembly factor complex subunit CHAF1B promotes leukemogenesis by interfering with chromatin occupancy of transcription factors that promote myeloid differentiation. Reducing CHAF1B activity suppresses leukemogenesis without impairing normal hematopoiesis.

AB - CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of histones H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele is sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis. Volk et al. show that overexpression of the chromatin assembly factor complex subunit CHAF1B promotes leukemogenesis by interfering with chromatin occupancy of transcription factors that promote myeloid differentiation. Reducing CHAF1B activity suppresses leukemogenesis without impairing normal hematopoiesis.

KW - CAF1

KW - CHAF1B

KW - MLL-AF9

KW - hematopoiesis

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A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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