Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation

Yuan Liang Zhang, Jie Wen Sun, Yin Yin Xie, Yan Zhou, Ping Liu, Jia Chun Song, Chun Hui Xu, Lan Wang, Dan Liu, Ai Ning Xu, Zhu Chen, Sai Juan Chen, Xiao Jian Sun, Qiu Hua Huang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets.

Original languageEnglish (US)
Pages (from-to)476-490
Number of pages15
JournalCell Research
Volume28
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Fingerprint

Hematopoietic Stem Cells
Carcinogenesis
Ribonucleotide Reductases
Cell Self Renewal
Gene Regulatory Networks
Genomic Instability
Myelodysplastic Syndromes
Hematopoiesis
Methyltransferases
Hematologic Neoplasms
DNA Replication
Transcriptome
Epigenomics
Knockout Mice
Histones
Lysine
Neoplasms
Cell Cycle
Leukemia
Transcription Factors

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Zhang, Y. L., Sun, J. W., Xie, Y. Y., Zhou, Y., Liu, P., Song, J. C., ... Huang, Q. H. (2018). Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Research, 28(4), 476-490. https://doi.org/10.1038/s41422-018-0015-9

Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. / Zhang, Yuan Liang; Sun, Jie Wen; Xie, Yin Yin; Zhou, Yan; Liu, Ping; Song, Jia Chun; Xu, Chun Hui; Wang, Lan; Liu, Dan; Xu, Ai Ning; Chen, Zhu; Chen, Sai Juan; Sun, Xiao Jian; Huang, Qiu Hua.

In: Cell Research, Vol. 28, No. 4, 01.04.2018, p. 476-490.

Research output: Contribution to journalArticle

Zhang, YL, Sun, JW, Xie, YY, Zhou, Y, Liu, P, Song, JC, Xu, CH, Wang, L, Liu, D, Xu, AN, Chen, Z, Chen, SJ, Sun, XJ & Huang, QH 2018, 'Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation', Cell Research, vol. 28, no. 4, pp. 476-490. https://doi.org/10.1038/s41422-018-0015-9
Zhang, Yuan Liang ; Sun, Jie Wen ; Xie, Yin Yin ; Zhou, Yan ; Liu, Ping ; Song, Jia Chun ; Xu, Chun Hui ; Wang, Lan ; Liu, Dan ; Xu, Ai Ning ; Chen, Zhu ; Chen, Sai Juan ; Sun, Xiao Jian ; Huang, Qiu Hua. / Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. In: Cell Research. 2018 ; Vol. 28, No. 4. pp. 476-490.
@article{d0dc4e2d80204296ab8bc54f2ef1d795,
title = "Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation",
abstract = "The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets.",
author = "Zhang, {Yuan Liang} and Sun, {Jie Wen} and Xie, {Yin Yin} and Yan Zhou and Ping Liu and Song, {Jia Chun} and Xu, {Chun Hui} and Lan Wang and Dan Liu and Xu, {Ai Ning} and Zhu Chen and Chen, {Sai Juan} and Sun, {Xiao Jian} and Huang, {Qiu Hua}",
year = "2018",
month = "4",
day = "1",
doi = "10.1038/s41422-018-0015-9",
language = "English (US)",
volume = "28",
pages = "476--490",
journal = "Cell Research",
issn = "1001-0602",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation

AU - Zhang, Yuan Liang

AU - Sun, Jie Wen

AU - Xie, Yin Yin

AU - Zhou, Yan

AU - Liu, Ping

AU - Song, Jia Chun

AU - Xu, Chun Hui

AU - Wang, Lan

AU - Liu, Dan

AU - Xu, Ai Ning

AU - Chen, Zhu

AU - Chen, Sai Juan

AU - Sun, Xiao Jian

AU - Huang, Qiu Hua

PY - 2018/4/1

Y1 - 2018/4/1

N2 - The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets.

AB - The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets.

UR - http://www.scopus.com/inward/record.url?scp=85043517309&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043517309&partnerID=8YFLogxK

U2 - 10.1038/s41422-018-0015-9

DO - 10.1038/s41422-018-0015-9

M3 - Article

AN - SCOPUS:85043517309

VL - 28

SP - 476

EP - 490

JO - Cell Research

JF - Cell Research

SN - 1001-0602

IS - 4

ER -