PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation

Zhihong Ren, Jeong Hyun Ahn, Hequn Liu, Yi Hsuan Tsai, Natarajan V. Bhanu, Brian Koss, David F. Allison, Anqi Ma, Aaron J. Storey, Ping Wang, Samuel G. Mackintosh, Ricky D. Edmondson, Richard W.J. Groen, Anton C. Martens, Benjamin A. Garcia, Alan J. Tackett, Jian Jin, Ling Cai, Deyou Zheng, Gang Greg Wang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Dysregulation of polycomb repressive complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19; also known as polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. Chromatin immunoprecipitation followed by sequencing profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains, possibly due to impaired H3K27me3 spreading from cytosine guanine dinucleotide islands, which is reminiscent to the reported effect of an “onco”-histone mutation, H3K27 to methionine (H3K27M). RNA-sequencing-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression. Correlation studies using patient sample data sets further support a clinical relevance of the PHF19-regulated pathways. Lastly, we show that MM cells are generally sensitive to PRC2 inhibitors. Collectively, this study demonstrates that PHF19 promotes MM tumorigenesis through enhancing H3K27me3 deposition and PRC2's gene-regulatory functions, lending support for PRC2 blockade as a means for MM therapeutics.

Original languageEnglish (US)
Pages (from-to)1176-1189
Number of pages14
JournalBlood
Volume134
Issue number14
DOIs
StatePublished - Oct 3 2019

Fingerprint

Polycomb Repressive Complex 2
Multiple Myeloma
Chemical activation
Histones
Chromatin
Tumors
Carcinogenesis
Genes
Plasma Cell Leukemia
RNA Sequence Analysis
Chromatin Immunoprecipitation
Gene Expression Profiling
Regulator Genes
Islands
Methionine
Interferons
Fingers
Lysine
Amplification
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ren, Z., Ahn, J. H., Liu, H., Tsai, Y. H., Bhanu, N. V., Koss, B., ... Wang, G. G. (2019). PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation. Blood, 134(14), 1176-1189. https://doi.org/10.1182/blood.2019000578

PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation. / Ren, Zhihong; Ahn, Jeong Hyun; Liu, Hequn; Tsai, Yi Hsuan; Bhanu, Natarajan V.; Koss, Brian; Allison, David F.; Ma, Anqi; Storey, Aaron J.; Wang, Ping; Mackintosh, Samuel G.; Edmondson, Ricky D.; Groen, Richard W.J.; Martens, Anton C.; Garcia, Benjamin A.; Tackett, Alan J.; Jin, Jian; Cai, Ling; Zheng, Deyou; Wang, Gang Greg.

In: Blood, Vol. 134, No. 14, 03.10.2019, p. 1176-1189.

Research output: Contribution to journalArticle

Ren, Z, Ahn, JH, Liu, H, Tsai, YH, Bhanu, NV, Koss, B, Allison, DF, Ma, A, Storey, AJ, Wang, P, Mackintosh, SG, Edmondson, RD, Groen, RWJ, Martens, AC, Garcia, BA, Tackett, AJ, Jin, J, Cai, L, Zheng, D & Wang, GG 2019, 'PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation', Blood, vol. 134, no. 14, pp. 1176-1189. https://doi.org/10.1182/blood.2019000578
Ren, Zhihong ; Ahn, Jeong Hyun ; Liu, Hequn ; Tsai, Yi Hsuan ; Bhanu, Natarajan V. ; Koss, Brian ; Allison, David F. ; Ma, Anqi ; Storey, Aaron J. ; Wang, Ping ; Mackintosh, Samuel G. ; Edmondson, Ricky D. ; Groen, Richard W.J. ; Martens, Anton C. ; Garcia, Benjamin A. ; Tackett, Alan J. ; Jin, Jian ; Cai, Ling ; Zheng, Deyou ; Wang, Gang Greg. / PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation. In: Blood. 2019 ; Vol. 134, No. 14. pp. 1176-1189.
@article{b2230b1f9e98492eb4b33a66112ff48f,
title = "PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation",
abstract = "Dysregulation of polycomb repressive complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19; also known as polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. Chromatin immunoprecipitation followed by sequencing profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains, possibly due to impaired H3K27me3 spreading from cytosine guanine dinucleotide islands, which is reminiscent to the reported effect of an “onco”-histone mutation, H3K27 to methionine (H3K27M). RNA-sequencing-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression. Correlation studies using patient sample data sets further support a clinical relevance of the PHF19-regulated pathways. Lastly, we show that MM cells are generally sensitive to PRC2 inhibitors. Collectively, this study demonstrates that PHF19 promotes MM tumorigenesis through enhancing H3K27me3 deposition and PRC2's gene-regulatory functions, lending support for PRC2 blockade as a means for MM therapeutics.",
author = "Zhihong Ren and Ahn, {Jeong Hyun} and Hequn Liu and Tsai, {Yi Hsuan} and Bhanu, {Natarajan V.} and Brian Koss and Allison, {David F.} and Anqi Ma and Storey, {Aaron J.} and Ping Wang and Mackintosh, {Samuel G.} and Edmondson, {Ricky D.} and Groen, {Richard W.J.} and Martens, {Anton C.} and Garcia, {Benjamin A.} and Tackett, {Alan J.} and Jian Jin and Ling Cai and Deyou Zheng and Wang, {Gang Greg}",
year = "2019",
month = "10",
day = "3",
doi = "10.1182/blood.2019000578",
language = "English (US)",
volume = "134",
pages = "1176--1189",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "14",

}

TY - JOUR

T1 - PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation

AU - Ren, Zhihong

AU - Ahn, Jeong Hyun

AU - Liu, Hequn

AU - Tsai, Yi Hsuan

AU - Bhanu, Natarajan V.

AU - Koss, Brian

AU - Allison, David F.

AU - Ma, Anqi

AU - Storey, Aaron J.

AU - Wang, Ping

AU - Mackintosh, Samuel G.

AU - Edmondson, Ricky D.

AU - Groen, Richard W.J.

AU - Martens, Anton C.

AU - Garcia, Benjamin A.

AU - Tackett, Alan J.

AU - Jin, Jian

AU - Cai, Ling

AU - Zheng, Deyou

AU - Wang, Gang Greg

PY - 2019/10/3

Y1 - 2019/10/3

N2 - Dysregulation of polycomb repressive complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19; also known as polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. Chromatin immunoprecipitation followed by sequencing profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains, possibly due to impaired H3K27me3 spreading from cytosine guanine dinucleotide islands, which is reminiscent to the reported effect of an “onco”-histone mutation, H3K27 to methionine (H3K27M). RNA-sequencing-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression. Correlation studies using patient sample data sets further support a clinical relevance of the PHF19-regulated pathways. Lastly, we show that MM cells are generally sensitive to PRC2 inhibitors. Collectively, this study demonstrates that PHF19 promotes MM tumorigenesis through enhancing H3K27me3 deposition and PRC2's gene-regulatory functions, lending support for PRC2 blockade as a means for MM therapeutics.

AB - Dysregulation of polycomb repressive complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19; also known as polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. Chromatin immunoprecipitation followed by sequencing profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains, possibly due to impaired H3K27me3 spreading from cytosine guanine dinucleotide islands, which is reminiscent to the reported effect of an “onco”-histone mutation, H3K27 to methionine (H3K27M). RNA-sequencing-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression. Correlation studies using patient sample data sets further support a clinical relevance of the PHF19-regulated pathways. Lastly, we show that MM cells are generally sensitive to PRC2 inhibitors. Collectively, this study demonstrates that PHF19 promotes MM tumorigenesis through enhancing H3K27me3 deposition and PRC2's gene-regulatory functions, lending support for PRC2 blockade as a means for MM therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=85072944010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072944010&partnerID=8YFLogxK

U2 - 10.1182/blood.2019000578

DO - 10.1182/blood.2019000578

M3 - Article

C2 - 31383640

AN - SCOPUS:85072944010

VL - 134

SP - 1176

EP - 1189

JO - Blood

JF - Blood

SN - 0006-4971

IS - 14

ER -